David Kotlyar

A Systematic Review of Factors That Contribute to Hepatosplenic T-Cell Lymphoma in Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS Hepatosplenic T-cell lymphoma (HSTCL) is a rare and usually fatal lymphoma that primarily affects men younger than 35 years old. Treatment of patients with inflammatory bowel disease (IBD) using antibodies to tumor necrosis factor (anti-TNFs) and thiopurines has been associated with HSTCL. We investigated the medications, duration of therapy, and ages of patients associated with HSTCL. METHODS We collected and analyzed data on the association between HSTCL, and anti-TNF and thiopurine therapies in patients with IBD from published reports and the MedWatch reporting system of the US Food and Drug Administration. RESULTS Of 36 patients with HSTCL, 20 received therapy with infliximab and a thiopurine and 16 received a thiopurine as monotherapy for IBD. Four patients who had been treated with infliximab and a thiopurine also received adalimumab. One of these patients had been given infliximab, adalimumab, and natalizumab. Of 31 patients of known gender, only 2 were female. Twenty-seven of the 30 patients of known age were younger than 35 years old. CONCLUSIONS Most patients with HSTCL who received long-term therapy (at least 2 y) with thiopurines for IBD were men younger than 35 years old. There were no reported cases of HSTCL in patients with IBD who received only anti-TNF therapy. Physicians should consider giving thiopurines and anti-TNF agents to young male patients with IBD only in cases in which a clear benefit is expected, such as in early stage disease in untreated patients or possibly in very severe cases.

Renal function after orthotopic liver transplantation is predicted by duration of pretransplantation creatinine elevation

In patients with recent onset renal insufficiency, the decision to perform combined kidney/liver transplantation (CKLT) vs. orthotopic liver transplantation alone (OLTa) can be difficult. We hypothesized that duration of renal dysfunction may correlate with creatinine elevation after liver transplantation. We retrospectively identified 69 liver transplantation patients with pretransplantation creatinine ≥1.5 mg/dL (53 OLTa, 13 CKLT). Variables analyzed were presence of hepatorenal syndrome, creatinine, Model for End‐Stage Liver Disease score, albumin, age, race, gender, cause of liver disease, diabetes mellitus, hypertension, and history of ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, renal replacement therapy (RRT), and transjugular intrahepatic portosystemic shunting. Duration of pretransplantation renal dysfunction was predictive of 6‐ and 12‐month creatinine post‐OLTa. Area under the receiver operating characteristic (ROC) curve for prediction of 12‐month renal insufficiency by renal dysfunction duration was 0.71; optimal duration cutoff was 3.6 weeks. We applied a multivariable model, derived from OLTa patients, to CKLT subjects with definite or possible hepatorenal syndrome. Predicted 12‐month creatinine without renal transplantation was >2.0 mg/dL for each patient. CKLT patients as opposed to OLTa patients had longer duration of renal dysfunction (median, 18.1 vs. 2.7 weeks, P < 0.001), higher creatinine (median 4.0 versus 1.7 mg/dL, P < 0.001), and higher rate of pretransplantation RRT (62% vs. 7%, P < 0.001). Adjusting for baseline characteristics, CKLT patients had lower creatinine than OLTa patients at 6 months (P =0.15) and 12 months (P =0.01) after transplantation. In conclusion, duration, but not cause, of renal dysfunction predicts renal outcome in OLTa recipients. Prospective studies may use duration of renal dysfunction to help identify CKLT candidates. (Liver Transpl 2005;11:1048–1055.)

A critical review of candidacy for orthotopic liver transplantation in alcoholic liver disease.

The majority of candidates with end-stage alcoholic liver disease (ESALD) in the United States who are eligible for referral for liver transplantation (LT) are not being referred. There is a lack of firm consensus for the duration of abstinence from alcohol as well as what constitutes good psychosocial criteria for listing for LT. Evidence shows that the general public and the practicing physicians outside the transplant community perceive that patients with a history of alcohol abuse will make poor transplant candidates. However, physicians in the transplant community perceive selected patients with ESALD as good candidates. When considering patients for listing for LT, 3 months of alcohol abstinence may be more ideal than 6 months. Patients with a lack of social support, active smoking, psychotic or personality disorders, or a pattern of nonadherence should be listed only with reservation. Those who have a diagnosis of alcohol abuse as opposed to alcohol dependence may make better transplant candidates. Patients who have regular appointments with a psychiatrist or psychologist in addictions treatment training also seem to do more favorably.

Recurrence of Diseases Following Orthotopic Liver Transplantation

Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disese recurrence.

Hepatosplenic T-Cell Lymphoma in Inflammatory Bowel Disease: A Possible Thiopurine-Induced Chromosomal Abnormality

Hepatosplenic T-Cell Lymphoma in Inflammatory Bowel Disease: A Possible Thiopurine-Induced Chromosomal Abnormality

Noninvasive monitoring of hepatitis C fibrosis progression.

Noninvasive approaches in the diagnosis and monitoring of fibrosis are still evolving. Transient elastography is an inexpensive, rapid, and relatively accurate form of noninvasive monitoring, especially in severe fibrosis It is a nascent technology, however, and there is no clear indication that elastography is better than biopsy for less severe fibrosis. With improved resolution and longer term data, it may become a vital supplement. The combined use of transient elastography and biochemical markers seems to be the most promising noninvasive technique.

Non-pulmonary allergic diseases and inflammatory bowel disease: a qualitative review.

While the etiological underpinnings of inflammatory bowel disease (IBD) are highly complex, it has been noted that both clinical and pathophysiological similarities exist between IBD and both asthma and non-pulmonary allergic phenomena. In this review, several key points on common biomarkers, pathophysiology, clinical manifestations and nutritional and probiotic interventions for both IBD and non-pulmonary allergic diseases are discussed. Histamine and mast cell activity show common behaviors in both IBD and in certain allergic disorders. IgE also represents a key immunoglobulin involved in both IBD and in certain allergic pathologies, though these links require further study. Probiotics remain a critically important intervention for both IBD subtypes as well as multiple allergic phenomena. Linked clinical phenomena, especially sinonasal disease and IBD, are discussed. In addition, nutritional interventions remain an underutilized and promising therapy for modification of both allergic disorders and IBD. Recommending new mothers breastfeed their infants, and increasing the duration of breastfeeding may also help prevent both IBD and allergic diseases, but requires more investigation. While much remains to be discovered, it is clear that non-pulmonary allergic phenomena are connected to IBD in a myriad number of ways and that the discovery of common immunological pathways may usher in an era of vastly improved treatments for patients.

Su1147 Meta-Analysis of Overall Risk of Lymphoma in Patients With Inflammatory Bowel Disease on Thiopurine Therapy With Inclusion of European and North American Studies: Differences Between Referral Center Studies and Population Based Studies

BackgroundWith the ever increasing use of immunosuppressive therapy for the management of inflammatory bowel disease (IBD), patients are being exposed to infections which can be prevented by vaccinations administered prior to or during therapy. The European Crohns and Colitis Organisation guidelines currently recommend that IBD patients who receive immunosuppressive medications should be vaccinated yearly with the influenza vaccine and a pneumococcal vaccination 3-5 yearly. Several studies have demonstrated that despite guidelines many patients were still not being vaccinated for preventable disease. Method An audit was carried out within our department to assess our patients knowledge and uptake of such vaccines. Patients were identified from an established database and those receiving immunosuppressive therapy were invited to complete a questionnaire. Data gathered included age, gender, current treatment, awareness and uptake of vaccinations. Results A cohort of 88 patients on immmunosuppressive therapy were analysed. 61% of patients were female and 39% male. Patients ranged between 16-21 years (11%), 22-30 years (18%), 31-50 years (40%), 51-70 years (24%) and above 70 (7%). 59 (67%) patients had Crohns disease, 26 (29.5%) ulcerative colitis and 3 (3.5%) had indeterminate colitis. The majority of patients received immunomodulators including Azathioprine or Mycophenolate (n=48, 54%). 13 (15%) were treated with biologics alone (Infliximab or Adalimumab), 21 (24%) with combination of biologics and immunomodulators and 6 patients (7%) received immunomodulators with a reducing dose of steroids. 77% of patients were aware of recommended vaccinations but as many as 23% were not. 42% were aware of the importance of receiving dual vaccinations, 35% only aware of either the influenza or pneumococcal vaccine, with 23% unaware of the need for either. 54 (61%) patients had already had or were planning to have the influenza vaccine this year. Patients between the ages of 31-50 years had the highest awareness of the recommended vaccines (86%), with the majority of uptake of vaccines seen in the 31-50 year group (63%). Unfortunately 39% of patients were not receiving recommended vaccinations with more than half (56%) of patients being unaware of the need to avoid live vaccinations. Conclusions Our data suggest that a significant proportion of patients within our cohort are still not receiving vaccinations that were recommended to them. Although 77 % were aware of a form of recommended vaccine, 39% were not receiving them. Wider education of our IBD patients as well as their primary care doctors should be implemented to increase awareness and uptake of vaccines to provide adequate protection to this vulnerable group.

Overall Incidence of Hepatosplenic T Cell Lymphoma in Patients With Inflammatory Bowel Disease on Thiopurines: A Meta-Analysis of Three Population Based Studies

Background: Hepatosplenic T-cell lymphoma is a feared complication of thiopurine treatment for Inflammatory Bowel Disease. While estimates of the risk of Hepatosplenic T-cell lymphoma have been stated in the past, it has not been possible to calculate an estimated incidence as no population based studies of patients with IBD on thiopurines has yet reported a case of HSTCL. Aims: Here we aim to calculate the incidence of HSTCL via a meta-analysis of three population based studies of IBD patients taking thiopurine therapy. We also aim to calculate the relative risk of HSTCL. Methods: We included three population based studies in our analysis, a study from the UK, (Armstrong 2010 Am J of Gastro), one from France (CESAME; Beaugerie 2009 Lancet), and one from Spain (Gisbert Gastro 2010). In our study data were extracted from the Spanish collaborative registry ENEIDA (of which the Gisbert study was published). We examined overall incidence, the incidence in men, those less than 36 years old, and men under 36 years old. 95% confidence intervals (CIs) were estimated by summing observed and expected cases of lymphoma. CIs assumed a Poisson distribution. To examine for heterogeneity, the deviance statistic from Poisson regression models was examined. All patient studies were in compliance with the Helsinki Protocol. Results: One case of HSTCL was present among the three studies, (in ENEIDA). The overall incidence was 1.32 cases per 100,000 person-years with a number needed to harm (NNH) of 1:75,488 patients per year. For men, the incidence was 2.69 cases per 100,000 person-years with an NNH of 1:37,208 per year, and in those under 36 years of age the incidence was 3.63 cases per 100,000 person years with an NNH of 1:27,528. In men under 36, the incidence was 7.93 cases per 100,000 person years with an NNH of 1:12,616 patients per year. Confidence intervals were very large secondary to only one patient being described and there was no significant heterogeneity (see Table 1). Conclusion: In a recent systematic review of HSTCL in IBD (Kotlyar 2010, Clin Gastroenterol Hepatol), while incidence could not be estimated, the absolute risk was estimated at being 1:44,444 overall and 1:7404 in men under 35. These estimates accord with calculated numbers needed to harm of 1:75,488 per year overall and 1:12,616 per year in men under 36. Confidence Interval for Incidence and Tests for Heterogeneity

Meta-analysis of risk for lymphoma with immunomodulators for inflammatory bowel disease.

e18517 Background: Inflammatory bowel disease (IBD) treatment includes immunomodulators (Kandiel 2005 PMID: 16009685). Here we pooled studies examining immunomodulators as a risk factor for lymphoma to increase the power of risk estimates. Methods: We searched MEDLINE for: lymphoproliferative and thiopurines; and azathioprine and lymphoma. Included citations were cohort studies examining IBD (ulcerative colitis and Crohns disease), evaluated cancer as an outcome, and pts. received AZA, and/or 6-MP. Pooled standardized incidence rates (SIRs) and 95% confidence intervals (CIs) were estimated by summing observed and expected numbers of lymphomas. CIs assumed a Poisson distribution. To examine for heterogeneity, the deviance statistic from Poisson regression models was examined. Results: There were 414 citations, and 406 were excluded. In referral centers (n=6), the SIR = 4.43. (95% CI: 2.53-7.21). In population-based studies (n=2), the SIR = 4.27 (95% CI: 2.52-6.75).There was no significant difference betwe...