Hamed Khalili

Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease

Introduction Dietary fats influence intestinal inflammation and regulate mucosal immunity. Data on the association between dietary fat and risk of Crohns disease (CD) and ulcerative colitis (UC) are limited and conflicting. Methods We conducted a prospective study of women enrolled in the Nurses’ Health Study cohorts. Diet was prospectively ascertained every 4 years using a validated semi-quantitative food frequency questionnaire. Self-reported CD and UC were confirmed through medical record review. We examined the effect of energy-adjusted cumulative average total fat intake and specific types of fat and fatty acids on the risk of CD and UC using Cox proportional hazards models adjusting for potential confounders. Results Among 170 805 women, we confirmed 269 incident cases of CD (incidence 8/100 000 person-years) and 338 incident cases of UC (incidence 10/100 000 person-years) over 26 years and 3 317 338 person-years of follow-up. Cumulative energy-adjusted intake of total fat, saturated fats, unsaturated fats, n-6 and n-3 polyunsaturated fatty acids (PUFAs) were not associated with risk of CD or UC. However, greater intake of long-chain n-3 PUFAs was associated with a trend towards lower risk of UC (HR 0.72, 95% CI 0.51 to 1.01). In contrast, high long-term intake of trans-unsaturated fatty acids was associated with a trend towards an increased incidence of UC (HR 1.34, 95% CI 0.94 to 1.92). Conclusions A high intake of dietary long-chain n-3 PUFAs may be associated with a reduced risk of UC. In contrast, high intake of trans-unsaturated fats may be associated with an increased risk of UC.

Use of Proton Pump Inhibitors and Risk of Hip Fracture in Relation to Dietary and Lifestyle Factors: A Prospective Cohort Study

Objective To examine the association between chronic use of proton pump inhibitors (PPIs) and risk of hip fracture. Design Prospective cohort study. Setting Nurses’ Health Study, which originally recruited from the 11 most populous states in the US. Participants 79 899 postmenopausal women enrolled in the Nurses’ Health Study who provided data on the use of PPIs and other risk factors biennially since 2000 and were followed up to 1 June 2008. Main outcome measure Incident hip fracture Results During 565 786 person years of follow-up, we documented 893 incident hip fractures. The absolute risk of hip fracture among regular users of PPIs was 2.02 events per 1000 person years, compared with 1.51 events per 1000 person years among non-users. Compared with non-users, the risk of hip fracture among women who regularly used PPIs for at least two years was 35% higher (age adjusted hazard ratio 1.35 (95% confidence interval 1.13 to 1.62)), with longer use associated with increasing risk (Ptrend<0.01). Adjustment for risk factors, including body mass index, physical activity, and intake of calcium did not materially alter this association (hazard ratio 1.36 (1.13 to 1.63)). These associations were also not changed after accounting for reasons for PPI use. The relation between PPI use and fracture differed by smoking history (Pinteraction=0.03). Among current and former smokers, PPI use was associated with greater than 50% increase in risk of fracture, with a multivariate hazard ratio for fracture of 1.51 (1.20 to 1.91). In contrast, among women who never smoked there was no association (multivariate hazard ratio 1.06 (0.77 to 1.46)). In a meta-analysis of these results with 10 prior studies, the pooled odds ratio of hip fracture associated with PPI use was 1.30 (1.25 to 1.36). Conclusion Chronic use of PPIs is associated with increased risk of hip fracture, particularly among women with a history of smoking.

Efficacy of Vedolizumab as Induction Therapy in Refractory IBD Patients: A Multicenter Cohort.

Background:Vedolizumab (VDZ) demonstrated efficacy in Crohns disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease in a multicenter cohort of patients. Methods:Patients at Massachusetts General Hospital and Brigham and Womens Hospital were considered for inclusion. VDZ (300 mg) was administered at weeks 0, 2, 6, and 14. Efficacy was assessed using the Harvey–Bradshaw index for CD, the simple clinical colitis activity index for UC and physician assessment, along with C-reactive protein and decrease of corticosteroid therapy. Clinical response was defined as decrease in Harvey–Bradshaw index ≥3 and simple clinical colitis activity index ≥3 and remission as Harvey–Bradshaw index ⩽4, simple clinical colitis activity index ⩽2 and physician assessment of response and remission. Results:Our study included 172 patients (107 CD, 59 UC, 6 inflammatory bowel disease-unclassified, men 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had ostomy and 9 ileoanal pouch, and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14, respectively. Adverse events occurred in 10.5%. Conclusions:VDZ is safe and well tolerated in refractory inflammatory bowel disease patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials.

Physical activity and risk of inflammatory bowel disease: prospective study from the Nurses’ Health Study cohorts

Objective To examine the association between physical activity and risk of ulcerative colitis and Crohn’s disease. Design Prospective cohort study. Setting Nurses’ Health Study and Nurses’ Health Study II. Participants 194 711 women enrolled in the Nurses’ Health Study and Nurses’ Health Study II who provided data on physical activity and other risk factors every two to four years since 1984 in the Nurses’ Health Study and 1989 in the Nurses’ Health Study II and followed up through 2010. Main outcome measure Incident ulcerative colitis and Crohn’s disease. Results During 3 421 972 person years of follow-up, we documented 284 cases of Crohn’s disease and 363 cases of ulcerative colitis. The risk of Crohn’s disease was inversely associated with physical activity (P for trend 0.02). Compared with women in the lowest fifth of physical activity, the multivariate adjusted hazard ratio of Crohn’s disease among women in the highest fifth of physical activity was 0.64 (95% confidence interval 0.44 to 0.94). Active women with at least 27 metabolic equivalent task (MET) hours per week of physical activity had a 44% reduction (hazard ratio 0.56, 95% confidence interval 0.37 to 0.84) in risk of developing Crohn’s disease compared with sedentary women with <3 MET h/wk. Physical activity was not associated with risk of ulcerative colitis (P for trend 0.46). The absolute risk of ulcerative colitis and Crohn’s disease among women in the highest fifth of physical activity was 8 and 6 events per 100 000 person years compared with 11 and 16 events per 100 000 person years among women in the lowest fifth of physical activity, respectively. Age, smoking, body mass index, and cohort did not significantly modify the association between physical activity and risk of ulcerative colitis or Crohn’s disease (all P for interaction >0.35). Conclusion In two large prospective cohorts of US women, physical activity was inversely associated with risk of Crohn’s disease but not of ulcerative colitis.

Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability.

Background & Aims Emerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism. Methods A meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells. Results Nonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)–induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury. Conclusions Our clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNFα and MLCK.

Early life factors and risk of inflammatory bowel disease in adulthood.

Background:Early life factors have been postulated to play a role in development of immune tolerance and intestinal microbiome, which in turn may influence the risk of inflammatory bowel disease. Methods:We conducted a prospective cohort study of 60,186 U.S. women enrolled since 1976 in the Nurses Health Study (NHS) I and 86,495 women enrolled since 1989 in the NHS II with no history of ulcerative colitis (UC) or Crohn’s disease (CD). Information about breastfeeding, birth weight, and preterm birth were collected in 1992 in NHS I and 1991 in NHS II. Diagnoses of CD and UC were confirmed through review of medical records. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. Results:Among 146,681 women over 3,373,726 person-years of follow-up, we documented 248 cases of CD and 304 cases of UC through 2007 in NHS II and 2008 in NHS I. The median age of diagnosis was 51 for CD and 49 for UC. Compared with women who were not breastfed, women who were breastfed had multivariate-adjusted hazard ratios of 0.99 (95% confidence interval, 0.76–1.30) for CD and 1.03 (95% confidence interval, 0.81–1.32) for UC. Similarly, low or high birth weight and preterm birth were not significantly associated with risk of UC or CD. Conclusions:In 2 large prospective cohorts of U.S. women, we did not observe a significant association between early life factors including having been breastfed, birth weight, preterm birth, and risk of adult-onset UC and CD.

ABO Blood Group and Risk of Colorectal Cancer

Background: Recent studies have shown an association between non-O blood group and risk of pancreatic cancer. It is unclear whether this association is observed with other gastrointestinal malignancies, including colorectal cancers. Methods: We examined the relationship between ABO blood group and the risk of incident colorectal cancer in two large prospective cohorts. We calculated HR using Cox proportional hazard modeling while adjusting for known risk factors of colorectal cancer. Results: During 996,779 person-years of follow-up, we documented 1,025 incident cases of colorectal cancers. Compared to individuals with blood group O, the multivariate-adjusted HR were 1.08 (95% CI, 0.94–1.24) for blood group A, 1.20 (95% CI, 1.00–1.45) for blood group B, and 1.08 (95% CI, 0.85–1.36) for blood group AB. Conclusion: In two large prospective cohorts, we did not observe a statistically significant association between ABO blood group and risk of colorectal cancer. Impact: These results do not support an association between ABO blood group and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 20(5); 1017–20. ©2011 AACR.

A Prospective Study of Bisphosphonate Use and Risk of Colorectal Cancer

PURPOSE Bisphosphonates are used for the treatment of bone metastases and have been associated with a lower risk of breast cancer. A recent case-control study showed an inverse association between bisphosphonate use and colorectal cancer. Data from prospective cohorts are lacking. PATIENTS AND METHODS We prospectively examined the relationship between bisphosphonate use and risk of colorectal cancer among 86,277 women enrolled onto the Nurses Health Study (NHS). Since 1998, participants have returned biennial questionnaires in which they were specifically queried about the regular use of bisphosphonates. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% CIs for risk of colorectal cancer. RESULTS Through 2008, we documented 801 cases of colorectal cancer over 814,406 person-years of follow-up. The age-adjusted HR for women who regularly used bisphosphonates was 0.92 (95% CI, 0.73 to 1.14) and was further attenuated after adjustment for other risk factors (multivariate HR, 1.04; 95% CI, 0.82 to 1.33). The risk was not influenced by duration of use (P(trend) = 0.79). Compared with nonusers, the multivariate-adjusted HRs of colorectal cancer were 1.24 (95% CI, 0.94 to 1.64) for women with 1 to 2 years of use, 1.16 (95% CI, 0.79 to 1.69) for 3 to 4 years of use, and 0.97 (95% CI, 0.60 to 1.56) for ≥ 5 years of use. There was no association between bisphosphonate use and colorectal cancer within strata of other risk factors. CONCLUSION In a large prospective cohort, we did not observe an association between long-term use of bisphosphonates and risk of colorectal cancer.

Multiple intracranial hydatidosis.

Summary. Background: Multiple intracranial hydatidosis (MIH) is a rare disease, with serious neurological manifestations, high recurrence and a mortality rate comparable sometimes to malignant disease. The causes of multiple infestations and their mechanisms are not clearly understood. Several attempts at classification are reported in the literature, but the diversity in location of these cysts in the brain and other organs, their appearance and recurrence rates remain largely unexplainable. Objective: Multiple intracranial hydatidosis (MIH) is reported in a series of patients to evaluate their incidence, localization, complications treatment and recurrences. In this study we tried to explain the mechanism of multiple infestations, and to propose a new classification. Methods: This was a retrospective study of thirty-four patients with MIH, treated between 1976 and 1999. The diagnosis was made mainly by CT scan and confirmed by surgery. MIH following iatrogenic rupture of a solitary cyst in the brain was excluded. Hydatid cysts were removed by the method described by Arana-Iñiguez (1973) using Dowlings technique. Histopathological examination was used to confirm the presence of scolices. The patients were followed-up for 3–14 years. Results: Twenty six patients (76.4%) were under the age of 20 years with a male to female ratio of 1.0:1.83. Clinically, patients with cysts exhibited features of increased intracranial pressure and focal neurological deficit. The cysts had a diameter between 2 to 120 millimeters. Histopathological examination showed that 63.6% of the cysts were fertile. Eleven patients (46.4%) achieved a good outcome. The operative mortality rate was 10.7%. Overall mortality was 17.6%. Five patients had more than one recurrence, which appeared after 3 months to 3 years. Conclusion: MIH are rare; to date only 77 reported cases have been encountered. To have such a high incidence in Iraq raises the possibility of a different strain of Echinococcus granulosis. A suggestion is made regarding terminology and classification.

New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease.

Anti‐tumour necrosis factor α (anti‐TNF) agents have been implicated in drug‐induced liver injury. There is minimal data on this occurrence in inflammatory bowel disease (IBD) patients.