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1.  [No title available] 
PMCID: PMC3962785  PMID: 24392888
2.  Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease 
Alimentary Pharmacology & Therapeutics  2013;38(10):1267-1277.
Background
Screening overweight and obese children for non-alcoholic fatty liver disease (NAFLD) is recommended by paediatric and endocrinology societies. However, gastroenterology societies have called for more data before making a formal recommendation.
Aim
To determine whether the detection of suspected NAFLD in overweight and obese children through screening in primary care and referral to paediatric gastroenterology resulted in a correct diagnosis of NAFLD.
Methods
Information generated in the clinical evaluation of 347 children identified with suspected NAFLD through screening in primary care and referral to paediatric gastroenterology was captured prospectively. Diagnostic outcomes were reported. The diagnostic performance of two times the upper limit of normal (ULN) for alanine aminotransferase (ALT) was assessed.
Results
Non-alcoholic fatty liver disease was diagnosed in 55% of children identified by screening and referral. Liver disease other than NAFLD was present in 18% of those referred. Autoimmune hepatitis was the most common alternative diagnosis. Children with NAFLD had significantly (P < 0.05) higher screening ALT (98 ± 95) than children with liver disease other than NAFLD (86 ± 74). Advanced fibrosis was present in 11% of children. For the diagnosis of NAFLD, screening ALT two times the clinical ULN had a sensitivity of 57% and a specificity of 71%.
Conclusions
Screening of overweight and obese children in primary care for NAFLD with referral to paediatric gastroenterology has the potential to identify clinically relevant liver pathology. Consensus is needed on how to value the risk and rewards of screening and referral, to identify children with liver disease in the most appropriate manner.
doi:10.1111/apt.12518
PMCID: PMC3984047  PMID: 24117728
3.  Randomised clinical trial: individualized versus weight-based dosing of azathioprine in crohn’s disease 
Background
Azathioprine (AZA), a pro-drug metabolized to the active metabolites 6-thioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn’s disease (CD). This trial investigated whether AZA therapy is optimized by individualized dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations.
Methods
This multicenter, double-blind, randomized controlled trial compared the efficacy and safety of weight-based vs. individualized AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16 weeks. In the weight-based arm, subjects received 2.5 mg/kg/d. In the individualized dosing arm, the initial AZA dose was 1.0 mg/kg/d (if intermediate TPMT) or 2.5 mg/kg/d (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250–400 pmol/8x108 red blood cells (RBC), or to a maximal dose of 4 mg/kg/d.
Results
After randomizing 50 subjects, the trial was stopped prematurely due to insufficient enrollment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualized arm vs. 16% in the weight-based arm (p=0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualized arm and 25% in the weight-based arm (p=0.12). At week 16, median 6TGN concentrations in PP remitters and non-remitters were 216 and 149 pmol/8x108 RBC respectively (p=0.07).
Conclusions
Despite trends favoring individualized over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualized arm.
doi:10.1111/apt.12555
PMCID: PMC3918445  PMID: 24237037
Azathioprine; thiopurine methyltransferase; dosing; Crohn’s disease
4.  Review article: vitamin d and inflammatory bowel diseases 
Alimentary pharmacology & therapeutics  2013;39(2):10.1111/apt.12553.
Background
Vitamin D is traditionally associated with bone metabolism. The immunologic effects of vitamin D have increasingly come into focus.
Aims
To review the evidence supporting a role of vitamin D in inflammatory bowel diseases.
Methods
A comprehensive search was performed on PubMed using the terms “crohn’s disease” “ulcerative colitis” and “vitamin D”
Results
Vitamin D deficiency is common in patients with IBD (16–95%) including those with recently diagnosed disease. Evidence supports immunologic role of vitamin D in IBD. In animal models, deficiency of vitamin D increases susceptibility to DSS colitis while 1,25(OH)2D3 ameliorates such colitis. One prospective cohort study found low predicted vitamin D levels to be associated with an increased risk of CD. Limited data also suggests an association between low vitamin D levels and increased disease activity, particularly in Crohn’s disease. In a large cohort, vitamin D deficiency (< 20ng/mL) was associated with increased risk of surgery (OR 1.8, 95% CI 1.2 – 2.5) in CD and hospitalizations in both CD (OR 2.1, 95% CI 1.6 – 2.7) and UC (OR 2.3, 95% CI 1.7 – 3.1). A single randomized controlled trial demonstrated that vitamin D supplementation may be associated with reduced frequency of relapses in patients with Crohn’s disease compared to placebo (13% vs. 29%, p = 0.06).
Conclusions
There is growing epidemiological evidence to suggest a role for vitamin D deficiency in the development of IBD and also its influence on disease severity. The possible therapeutic role of vitamin D in patients with IBD merits continued investigation.
doi:10.1111/apt.12553
PMCID: PMC3872479  PMID: 24236989
vitamin D; Crohn’s disease; ulcerative colitis; innate immunity; macrophage; autophagy
5.  The effects of aging on the onset and persistence of unexplained abdominal pain: a population-based study 
Background
The population ≥65 years is rapidly increasing but remarkably little is known about the natural history of abdominal pain with aging.
Aim
To prospectively evaluate the natural history of abdominal pain (severity and frequency) in a US population, and evaluate potential risk factors (including somatization) for the onset and disappearance of abdominal pain with increasing age.
Methods
Between 1988 and 2004, valid self-report questionnaires that recorded gastrointestinal symptoms including severity and frequency of abdominal pain were mailed to randomly selected cohorts of community residents followed over time. This study identified all respondents who answered abdominal pain questions at an initial and follow-up survey.
Results
1913 subjects were included (mean age in years at first survey: 48±12 (SD), mean age at second survey: 59±13 (SD); 53% female). The onset and disappearance rate of abdominal pain over the follow up were 14% (95% CI, 13,16) and 47% (43,50), respectively. The rates of increasing vs. decreasing abdominal pain score were 18% (16,20) vs. 22% (20,23), respectively. While younger age at initial survey was associated with onset of abdominal pain (vs. subjects without abdominal pain, [OR 0.9 (0.7,1.0)], older age at initial survey and times between surveys were associated with the disappearance of abdominal pain (vs. subjects with abdominal pain, [OR 1.2 (1.0,1.5)]. Female gender [OR 1.4 (1.0,2.1)], higher somatization scores and larger changes in somatization score [OR 5.3 (3.2,8.7)] were positively associated with the onset of abdominal pain.
Conclusions
Increasing age is associated with the disappearance of abdominal pain in the community.
doi:10.1111/apt.12557
PMCID: PMC4070656  PMID: 24304163
6.  Gut-directed hypnotherapy significantly augments clinical remission in quiescent ulcerative colitis 
Summary
Background
Psychotherapy is not routinely recommended for in ulcerative colitis (UC). Gut-directed hypnotherapy (HYP) has been linked to improved function in the gastrointestinal tract and may operate through immune-mediated pathways in chronic diseases.
Aims
To determine the feasibility and acceptability of hypnotherapy and estimate the impact of hypnotherapy on clinical remission status over a 1 year period in patients with an historical flare rate of 1.3 times per year.
Methods
54 patients were randomized at a single site to 7 sessions of gut-directed hypnotherapy (N = 26) or attention control (CON; N = 29) and followed for 1 year. The primary outcome was the proportion of participants in each condition that had remained clinically asymptomatic (clinical remission) through 52 weeks post-treatment.
Results
One-way ANOVA comparing hypnotherapy and control subjects on number of days to clinical relapse favored the hypnotherapy condition [F = 4.8 (1, 48), p = .03] by 78 days. Chi square analysis comparing the groups on proportion maintaining remission at 1 year was also significant [X2(1) = 3.9, p = .04], with 68% of hypnotherapy and 40% of control patients maintaining remission for 1 year. There were no significant differences between groups over time in quality of life, medication adherence, perceived stress or psychological factors.
Conclusions
This is the first prospective study that has demonstrated a significant effect of a psychological intervention on prolonging clinical remission in patients with quiescent UC.
Clinical Trial # NCT00798642
doi:10.1111/apt.12449
PMCID: PMC4271841  PMID: 23957526
ulcerative colitis; hypnotherapy; remission; inflammatory bowel disease; psychological treatment
7.  Thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease: relapse and recapture rates, with predictive factors in 237 patients 
Alimentary Pharmacology & Therapeutics  2014;40(11-12):1313-1323.
Background
Thiopurines (azathioprine and mercaptopurine) remain integral to most medical strategies for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Indefinite use of these drugs is tempered by long-term risks. While clinical relapse is noted frequently following drug withdrawal, there are few published data on predictive factors.
Aim
To investigate the success of planned thiopurine withdrawal in patients in sustained clinical remission to identify rates and predictors of relapse.
Methods
This was a multicentre retrospective cohort study from 11 centres across the UK. Patients included had a definitive diagnosis of IBD, continuous thiopurine use ≥3 years and withdrawal when in sustained clinical remission. All patients had a minimum of 12 months follow-up post drug withdrawal. Primary and secondary end points were relapse at 12 and 24 months respectively.
Results
237 patients were included in the study (129 CD; 108 UC). Median duration of thiopurine use prior to withdrawal was 6.0 years (interquartile range 4.4–8.4). At follow-up, moderate/severe relapse was observed in 23% CD and 12% UC patients at 12 months, 39% CD and 26% UC at 24 months. Relapse rate at 12 months was significantly higher in CD than UC (P = 0.035).
Elevated CRP at withdrawal was associated with higher relapse rates at 12 months for CD (P = 0.005), while an elevated white cell count was predictive at 12 months for UC (P = 0.007).
Conclusion
Thiopurine withdrawal in the context of sustained remission is associated with a 1-year moderate-to-severe relapse rate of 23% in Crohn's disease and 12% in ulcerative colitis.
doi:10.1111/apt.12980
PMCID: PMC4232866  PMID: 25284134
8.  Systematic review: interactions between aspirin, and other nonsteroidal anti-inflammatory drugs, and polymorphisms in relation to colorectal cancer 
Background
Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin (acetylsalicylic acid, ASA). Long-term use of NSAIDs has been associated with lowered risk of colorectal cancer (CRC), but the use is hampered by adverse effects. Also, the anti-carcinogenic effects of NSAIDs are incompletely understood. Understanding biological effects of NSAIDs may help developing new preventive medical strategies.
Aim
To identify gene–environment interactions between genetic variation and NSAID use in relation to risk of CRC.
Methods
We performed a PubMed literature search and all studies reporting original data on interactions between NSAIDs and polymorphisms in relation to CRC were evaluated.
Results
We found indications that aspirin interacted with rs6983267 close to MYC (encoding a transcription factor involved in cell cycle progression, apoptosis and cellular transformation) and NSAIDs interacted with rs3024505 and rs1800872 in or close to IL10 (encoding IL-10) in preventing CRC. Homozygous carriers of the variant allele of rs6983267 (ca. 25% of the population) halved their risk for CRC by aspirin use compared to homozygous wildtype carriers who did not benefit from aspirin intake. No interaction between use of NSAIDs and PTGS-2 (encoding COX-2) in relation to CRC risk was detected. Other findings of interactions between genes in inflammatory and oncogenic pathways and NSAIDs were considered suggestive.
Conclusions
Knowledge of underlying biological effects of NSAIDs in relation to CRC is scarce and the basis for stratifying the patients for preventive treatment is not yet available. Further studies assessing interactions between long-term NSAID exposure and genetic variation in relation to CRC are warranted in large well-characterised prospective cohorts.
doi:10.1111/apt.12807
PMCID: PMC4225470  PMID: 24889212
9.  Pediatric Gastroenterology Evaluation of Overweight and Obese Children Referred from Primary Care for Suspected Nonalcoholic Fatty Liver Disease 
Alimentary pharmacology & therapeutics  2013;38(10):1267-1277.
Background
Screening overweight and obese children for nonalcoholic fatty liver disease (NAFLD) is recommended by pediatric and endocrinology societies. However, gastroenterology societies have called for more data before making a formal recommendation.
Aim
To determine whether the detection of suspected NAFLD in overweight and obese children through screening in primary care and referral to pediatric gastroenterology, resulted in a correct diagnosis of NAFLD.
Methods
Information generated in the clinical evaluation of 347 children identified with suspected NAFLD through screening in primary care and referral to pediatric gastroenterology was captured prospectively. Diagnostic outcomes were reported. The diagnostic performance of two times the upper limit of normal for alanine aminotransferase (ALT) was assessed.
Results
NAFLD was diagnosed in 55% of children identified by screening and referral. Liver disease other than NAFLD was present in 18% of those referred. Autoimmune hepatitis was the most common alternate diagnosis. Children with NAFLD had significantly (p<0.05) higher screening ALT (98±95) than children with liver disease other than NAFLD (86±74). Advanced fibrosis was present in 11% of children. For the diagnosis of NAFLD, screening ALT two times the clinical upper limit of normal had a sensitivity of 57% and a specificity of 71%.
Conclusions
Screening of overweight and obese children in primary care for NAFLD with referral to pediatric gastroenterology has the potential to identify clinically relevant liver pathology. Consensus is needed on how to value the risk and rewards of screening and referral in order to identify children with liver disease in the most appropriate manner.
doi:10.1111/apt.12518
PMCID: PMC3984047  PMID: 24117728
11.  Meta analysis: underutilization and disparities of treatment among patients with hepatocellular carcinoma in the united states 
Background
Despite wide availability of treatment options for hepatocellular carcinoma (HCC), several studies have suggested underutilization in clinical practice.
Aims
To quantify utilization rates for HCC treatment among patients with HCC in the United States and summarize patterns of association between utilization rates and patient socio-demographic characteristics.
Methods
We performed a systematic literature review using the Medline database from January 1989 through March 2013. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled treatment rates for any treatment and curative treatment, with 95% confidence intervals, were calculated. Pre-specified subgroup analysis was performed to identify patient-level correlates of treatment utilization.
Results
We identified 24 studies that met inclusion criteria. The pooled rates of any treatment and curative treatment were 52.8% (95%CI 52.2-53.4%) and 21.8% (95%CI 21.4-22.1%) respectively. Among patients diagnosed at an early stage, the pooled curative treatment rate was 59.0% (95%CI 58.1-59.9%). Elderly, non-Caucasians and patients of low socioeconomic status had lower treatment rates than their counterparts.
Conclusions
Rates of HCC treatment in the United States, including curative treatment rates among patients detected at an early stage, are disappointingly low. Future efforts should focus on identifying appropriate intervention targets to increase treatment rates and reduce socio-demographic disparities.
doi:10.1111/apt.12450
PMCID: PMC3777750  PMID: 23957569
Hepatocellular carcinoma; treatment; socio-demographic disparities; United States
12.  Carbon monoxide in gastrointestinal physiology and its potential in therapeutics 
Background
While carbon monoxide (CO) is a known toxin, it is now recognized that CO is also an important signaling molecule involved in physiology and pathophysiology.
Aims
To summarize our current understanding of the role of endogenous CO in the regulation of gastrointestinal physiology and pathophysiology and potential therapeutic applications of modulating CO.
Methods
This review is based on a comprehensive search of the Ovid Medline comprehensive database and supplemented by our ongoing studies evaluating the role of CO in gastrointestinal physiology and pathophysiology.
Results
CO derived from heme oxygenase-2 is predominantly involved in neuromodulation and in setting the smooth muscle membrane potential while CO derived from heme oxygenase-1 has anti-inflammatory and anti-oxidative properties which protect gastrointestinal smooth muscle from damage caused by injury or inflammation. Exogenous CO is being explored as a therapeutic agent in a variety of gastrointestinal disorders including diabetic gastroparesis, postoperative ileus, organ transplantation, inflammatory bowel disease and sepsis. However, identifying the appropriate mechanism for safely delivering CO in humans is a major challenge.
Conclusions
CO is an important regulator of gastrointestinal function and protects the gastrointestinal tract against noxious injury. CO is a promising therapeutic target in conditions associated with gastrointestinal injury and inflammation. Elucidating the mechanisms by which CO works and developing safe CO delivery mechanisms are necessary to refine therapeutic strategies.
doi:10.1111/apt.12467
PMCID: PMC3788684  PMID: 23992228
Gastroparesis; Ileus; Transplantation; Macrophages; Inflammatory Bowel Disease; Heme oxygenase; cGMP; Sepsis; Gastrointestinal motility
13.  Dietary consumption of meat, fat, animal products and advanced glycation end-products and the risk of barrett’s esophagus 
Alimentary pharmacology & therapeutics  2013;38(7):10.1111/apt.12459.
Background
Advanced glycation end-products (AGEs) are found in high quantity in high-fat foods and meat cooked at high temperature. AGEs have been shown to contribute to chronic inflammation and oxidative stress in humans.
Aim
To investigate the associations between consumption of meat, fat and AGEs, and risk of Barrett’s esophagus (BE).
Methods
We conducted a case-control study using data from the patients who were scheduled for elective esophagogastroduodenoscopy (EGD) and from a random sample of patients who were identified at primary care clinics. Daily consumption of meat, fat and Nε-(carboxymethyl) lysine (CML), a major type of AGEs, was derived from the food frequency questionnaire (FFQ). Multivariate logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI) for BE.
Results
A total of 151 cases with BE and 777 controls without BE completed the FFQ. The multivariate OR (95% CI) for BE was 1.91 (1.07–3.38) for total meat, 1.80 (1.02–3.16) for saturated fat, and 1.63 (0.96–2.76) for CML-AGE, when the highest tertile of intake was compared with the lowest. The association for total meat was attenuated to 1.61 (0.82–3.16), and that for saturated fat to 1.54 (0.81–2.94) after adjusting for CML-AGE.
Conclusions
Higher consumption of total meat, saturated fat or possibly CML-AGE was associated with an increased risk of BE. CML-AGE may partly explain the association between total meat and saturated fat consumption and risk of BE.
doi:10.1111/apt.12459
PMCID: PMC3811083  PMID: 23957669
diet; barrette’s esophagus; risk factor; epidemiology
14.  Meta-analysis: antibiotic therapy for small intestinal bacterial overgrowth 
Alimentary pharmacology & therapeutics  2013;38(8):10.1111/apt.12479.
Background
Small intestinal bacterial overgrowth (SIBO) is an under-recognized diagnosis with important clinical implications when untreated. However, optimal treatment regimen remains unclear.
Aim
Systematic review and meta-analysis to compare clinical effectiveness of antibiotic therapies for treatment of symptomatic patients with documented SIBO.
Methods
Four databases were searched to identify clinical trials comparing effectiveness of: (1) different antibiotics, (2) different doses of the same antibiotic, and (3) antibiotics compared with placebo. Data were independently extracted according to predetermined inclusion and exclusion criteria. Study quality was independently assessed. Primary outcome was normalization of post-treatment breath testing. Secondary outcome was post-treatment clinical response.
Results
Of 1,356 articles identified, ten met inclusion criteria. Rifaximin was the most commonly studied antibiotic (8 studies) with overall breath test normalization rate of 49.5% (95% CI 44.0–55.1). Antibiotic efficacy varied by antibiotic regimen and dose. Antibiotics were more effective than placebo, with a combined breath test normalization rate of 51.1% (95% CI 46.7–55.5) for antibiotics compared with 9.8% (95% CI 4.6–17.8) for placebo. Meta-analysis of 4 studies favored antibiotics over placebo for breath test normalization with odds ratio 2.55 (95% CI 1.29–5.04). Clinical response was heterogeneously evaluated among six studies, but tended to correlate with breath test normalization.
Conclusions
Antibiotics appear to be more effective than placebo for breath test normalization in patients with symptoms attributable to SIBO, and breath test normalization may correlate with clinical response. Studies were limited by modest quality, small sample size, and heterogeneous design. Additional higher-quality clinical trials of SIBO therapy are warranted.
doi:10.1111/apt.12479
PMCID: PMC3819138  PMID: 24004101
small intestinal bacterial overgrowth; antibiotics; meta-analysis; systematic review
15.  Meta-analysis: the impact of disease activity at conception on disease activity during pregnancy in patients with inflammatory bowel disease 
SUMMARY
Background
The rate of IBD exacerbation during pregnancy varies in the published literature.
Aim
We sought to perform a systematic review and meta-analysis of the effects of disease activity at conception on disease course during pregnancy in women with IBD.
Methods
Published studies and abstracts from standard sources were screened for appropriate studies. Data was pooled and analyzed using funnel and forest plots. Quality assessment scores were given using GRADE criteria.
Results
Fourteen studies were eligible for inclusion; ten studies contained patients with UC (N=1130), and six studies contained patients with CD (N=590). In patients with UC there was a significantly higher risk ratio of active disease during pregnancy in patients who commenced pregnancy with active disease (55%), when compared with those in remission at conception (36%) (RR 2.0, 95% CI: 1.5–3, p<0.001). This risk was also higher in patients with CD, (RR 2.0, 95% CI: 1.2–3.4, p=0.006). Thirteen of the studies rated “low” in all domains of a quality assessment, and there was significant statistical heterogeneity.
Conclusions
Patients with IBD who conceive when their disease is active are more likely to have active disease during pregnancy than those who conceive when in remission. All studies used in this analysis had a high risk of bias therefore further studies are required.
doi:10.1111/apt.12417
PMCID: PMC3749828  PMID: 23855477
pregnancy; ulcerative colitis; Crohn’s; meta-analysis
16.  genetic risk factors for clostridium difficile infection in Ulcerative Colitis 
Introduction
Patients with inflammatory bowel disease (IBD) are at higher risk for Clostridium difficile infection (CDI). Disruption of gut microbiome and interaction with the intestinal immune system are essential mechanisms for pathogenesis of both CDI and IBD. Whether genetic polymorphisms associated with susceptibility to IBD are also associated with risk of CDI is unknown.
Methods
We used a prospective registry of patients from a tertiary referral hospital. Medical record review was performed to identify all ulcerative colitis (UC) patients within the registry with a history of CDI. All patients were genotyped on the Immunochip. We examined the association between the 163 risk loci for IBD and risk of CDI using a dominant genetic model. Model performance was examined using receiver operating characteristics curves.
Results
The study included 319 patients of whom 29 developed CDI (9%). Female gender and pancolitis were associated with increased risk while use of anti-TNF was protective against CDI. Six genetic polymorphisms including those at TNFRSF14 (Odds ratio (OR) 6.0, p-value 0.01) were associated with increased risk while 2 loci were inversely associated. On multivariate analysis, none of the clinical parameters retained significance after adjusting for genetics. Presence of at least one high risk locus was associated with an increase in risk for CDI (20% vs. 1%) (p=6 × 10−9). Compared to 11% for a clinical model, the genetic loci explained 28% of the variance in CDI risk and had a greater AUROC.
Conclusion
Host genetics may influence susceptibility to CDI in patients with ulcerative colitis.
doi:10.1111/apt.12425
PMCID: PMC3755009  PMID: 23848254
Clostridium difficile; ulcerative colitis; tumor necrosis factor; colectomy; genetics
17.  Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir 
SUMMARY
Background
Data about adverse events are needed to optimise telaprevir-based therapy in a broad spectrum of patients.
Aim
To investigate adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis in a real-world setting.
Methods
Data on 174 hepatitis C-infected patients initiating telaprevir-based therapy at Mount Sinai and Montefiore medical centres were collected. Biopsy data and FIB-4 scores identified patients with advanced fibrosis. Multivariable fully adjusted models were built to assess the effect of advanced fibrosis on specific adverse events and discontinuation of treatment due to an adverse event.
Results
Patients with (n = 71) and without (n = 103) advanced fibrosis were similar in BMI, ribavirin exposure, gender, prior treatment history, haemoglobin and creatinine, but differed in race. Overall, 47% of patients completed treatment and 40% of patients achieved SVR. Treated patients with and without advanced fibrosis or cirrhosis had similar rates of adverse events; advanced fibrosis, however, was independently associated with ano-rectal discomfort (P = 0.03). Three patients decompensated and had advanced fibrosis. The discontinuation of all treatment medications due to an adverse event was significantly associated with older age (P = 0.01), female gender (P = 0.01) and lower platelets (P = 0.03).
Conclusions
Adverse events were common, but were not significantly related to the presence of advanced fibrosis or cirrhosis. More critical monitoring in older and female patients with low platelets throughout treatment may reduce adverse event-related discontinuations.
doi:10.1111/apt.12560
PMCID: PMC4141692  PMID: 24266536
19.  Association between novel MRI-estimated pancreatic fat and liver histology-determined steatosis and fibrosis in nonalcoholic fatty liver disease 
SUMMARY
Background
Ectopic fat deposition in the pancreas and its association with hepatic steatosis have not previously been examined in patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD).
Aim
To quantify pancreatic fat using a novel magnetic resonance imaging (MRI) technique and determine whether it is associated with hepatic steatosis and/or fibrosis in patients with NAFLD.
Methods
This is a cross-sectional study including 43 adult patients with biopsy-proven NAFLD who underwent clinical evaluation, biochemical testing and MRI. The liver biopsy assessment was performed using the NASH-CRN histological scoring system, and liver and pancreas fat quantification was performed using a novel, validated MRI biomarker; the proton density fat fraction.
Results
The average MRI-determined pancreatic fat in patients with NAFLD was 8.5% and did not vary significantly between head, body, and tail of the pancreas. MRI-determined pancreatic fat content increased significantly with increasing histology-determined hepatic steatosis grade; 4.6% in grade 1; 7.7% in grade 2; 13.0% in grade 3 (P = 0.004) respectively. Pancreatic fat content was lower in patients with histology-determined liver fibrosis than in those without fibrosis (11.2% in stage 0 fibrosis vs. 5.8% in stage 1–2 fibrosis, and 6.9% in stage 3–4 fibrosis, P = 0.013). Pancreatic fat did not correlate with age, body mass index or diabetes status.
Conclusions
In patients with NAFLD, increased pancreatic fat is associated with hepatic steatosis. However, liver fibrosis is inversely associated with pancreatic fat content. Further studies are needed to determine underlying mechanisms to understand if pancreatic steatosis affects progression of NAFLD.
doi:10.1111/apt.12237
PMCID: PMC4136524  PMID: 23383649
20.  Non-selective beta-blockers are not associated with serious infections in veterans with cirrhosis 
SUMMARY
Background and Aim
Studies evaluating outcomes associated with nonselective beta-blockers (NSBB) in cirrhosis have yielded mixed results A major cause of death in decompensated cirrhosis is infection. We aimed to determine the effect of NSBB use on serious infections(requiring hospitalization) in compensated and decompensated cirrhosis.
Methods
Using data from the US Veterans Health Administration from 2001–2009, we identified two cohorts: 1) compensated (n=12,656) and 2) decompensated cirrhotics (n=4,834). From each cohort, we identified new NSBB users and propensity-matched them 1:1 to non-users (n=1,836 each in compensated users/non-users and n=1,462 each in decompensated users/non-users). They were followed for serious infections(median time: 3.1 years), death and transplant. We estimated adjusted hazard ratios(HR) and 95% confidence intervals(CI) from Cox regression models.
Results
Death or transplantation occurred in 0.7% compensated and 2.7% of decompensated patients. Among decompensated cirrhotics, death (p=0.0061) and transplantation (p=0.0086) occurred earlier in NSBB users compared to non-users. Serious infections were observed in 4.8% compensated and 13.7% of decompensated cirrhotics. There was no difference in the rate of serious infection development in new NSBB users compared to non-users in the compensated (adjusted HR: 0.90, CI:0.59–1.36) or in the decompensated group (adjusted HR: 1.10, CI: 0.96–1.25).
Conclusion
Non-selective beta-blockers use in U.S. veterans is not associated with an increased rate of serious infections in compensated or decompensated cirrhosis.
doi:10.1111/apt.12382
PMCID: PMC3725127  PMID: 23786291
beta blockers; cirrhosis; infections; survival; end-stage liver disease
21.  Characterizing abdominal pain in IBS: guidance for study inclusion criteria, outcome measurement and clinical practice 
SUMMARY
Background
Although irritable bowel syndrome (IBS) is a multisymptom disorder, abdominal pain drives illness severity more than other symptoms. Despite consensus that IBS trials should measure pain to define study entry and determine efficacy, the optimal method of measuring pain remains uncertain.
Aim
To determine whether combining information from multiple pain dimensions may capture the IBS illness experience more effectively than the approach of measuring `pain predominance' or pain intensity alone.
Methods
Irritable bowel syndrome patients rated dimensions of pain, including intensity, frequency, constancy, predominance, predictability, duration, speed of onset and relationship to bowel movements. We evaluated the impact of each dimension on illness severity using multivariable regression techniques.
Results
Among the pain dimensions, intensity, frequency, constancy and predictability were strongly and independently associated with illness severity; the other dimensions had weaker associations. The clinical definition of `pain predominance', in which patients define pain as their most bothersome symptom, was insufficient to categorize patients by illness severity.
Conclusions
Irritable bowel disease pain is multifaceted; some pain dimensions drive illness more than others. IBS trials should measure various pain dimensions, including intensity, constancy, frequency and predictability; this may improve upon the customary use of measuring pain as a unidimensional symptom in IBS.
doi:10.1111/j.1365-2036.2010.04443.x
PMCID: PMC4118306  PMID: 20807217
22.  Association between high dietary intake of the n−3 polyunsaturated fatty acid docosahexaenoic acid and reduced risk of Crohn's disease 
Summary
Background
There are plausible mechanisms for how dietary docosahexaenoic acid (DHA), an n−3 polyunsaturated fatty acid, could prevent Crohn's disease (CD).
Aim
To conduct a prospective study to investigate the association between increased intake of DHA and risk of CD.
Methods
Overall, 229 702 participants were recruited from nine European centres between 1991 and 1998. At recruitment, dietary intakes of DHA and fatty acids were measured using validated food frequency questionnaires. The cohort was monitored through to June 2004 to identify participants who developed incident CD. In a nested case–control analysis, each case was matched with four controls; odds ratios (ORs) were calculated for quintiles of DHA intake, adjusted for total energy intake, smoking, other dietary fatty acids, dietary vitamin D and body mass index.
Results
Seventy‐three participants developed incident CD. All higher quintiles of DHA intake were inversely associated with development of CD; the highest quintile had the greatest effect size (OR = 0.07; 95% CI = 0.02–0.81). The OR trend across quintiles of DHA was 0.54 (95% CI = 0.30–0.99, Ptrend = 0.04). Including BMI in the multivariate analysis, due to its correlation with dietary fat showed similar associations. There were no associations with the other dietary fatty acids studied.
Conclusion
There were inverse associations, with a biological gradient between increasing dietary docosahexaenoic acid intakes and incident Crohn's disease. Further studies in other populations should measure docosahexaenoic acid to determine if the association is consistent and the hypothesis tested in randomised controlled trials of purely docosahexaenoic acid supplementation.
doi:10.1111/apt.12670
PMCID: PMC4114542  PMID: 24611981
23.  Effect of hypnotherapy and educational intervention on brain response to visceral stimulusin the irritable bowel syndrome 
Alimentary pharmacology & therapeutics  2013;37(12):1184-1197.
SUMMARY
Background
Gut directed hypnotherapy can reduce IBS symptoms but the mechanisms underlying this therapeutic effect remain unknown.
Aim
We determined the effect of hypnotherapy and educational intervention on brain responses to cued rectal distensions in IBS patients.
Methods
44 women with moderate to severe IBS and 20 healthy controls (HCs) were included. Blood oxygen level dependent (BOLD) signals were measured by functional Magnetic Resonance Imaging (fMRI) during expectation and delivery of high (45 mmHg) and low (15 mmHg) intensity rectal distensions. Twenty-five patients were assigned to hypnotherapy (HYP) and 16 to educational intervention (EDU). 31 patients completed treatments and post treatment fMRI.
Results
Similar symptom reduction was achieved in both groups. Clinically successful treatment (all responders) was associated with significant BOLD attenuation during high intensity distension in the dorsal and ventral anterior insula (cluster size 142, p=0.006, and cluster size 101, p=0.005, respectively). Moreover HYP responders demonstrated a pre-post treatment BOLD attenuation in posterior insula (cluster sizes 59, p=0.05) while EDU responders had a BOLD attenuation in prefrontal cortex (cluster size 60, p=0.05). Pre-post differences for expectation conditions were almost exclusively seen in the HYP group. Following treatment, the brain response to distension was similar to that observed in HCs, suggesting that the treatment had a normalizing effect on the central processing abnormality of visceral signals in IBS.
Conclusions
The abnormal processing and enhanced perception of visceral stimuli in IBS can be normalized by psychological interventions. Symptom improvement in the treatment groups may be mediated by different brain mechanisms.
doi:10.1111/apt.12319
PMCID: PMC4084976  PMID: 23617618
24.  Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis 
Alimentary pharmacology & therapeutics  2013;38(2):10.1111/apt.12352.
SUMMARY
Background
Non-alcoholic steatohepatitis (NASH) is a common cause of serum alanine aminotransferase (ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations reflect the liver injury.
Aim
To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy.
Methods
The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non-alcoholic Steatohepatitis (PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to ≤40 U/L and by ≥30% of baseline. Liver biopsies taken before and after treatment were scored for non-alcoholic fatty liver disease activity (NAS) and fibrosis.
Results
ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients (P < 0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS (P < 0.001), but not fibrosis scores (P = 0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both (P < 0.05). Weight loss (≥2 kg) was also associated with ALT response (P < 0.001), improvements in NAS (P < 0.001) and fibrosis (P < 0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (≥2 kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E.
Conclusions
Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. Clinical Trial Number: NCT00063622.
doi:10.1111/apt.12352
PMCID: PMC3775262  PMID: 23718573
25.  The association between serological and dietary vitamin d levels and hepatitis c-related liver disease risk differs in african american and white males 
Background
Vitamin D may affect the severity of HCV-related liver disease. We examined the association between serum vitamin D levels and advanced liver disease in a multiethnic U.S. cohort of HCV patients, and accounted for dietary and supplemental intake.
Methods
We measured serum 25-hydroxyvitamin D levels and FibroSURE-ActiTest to assess hepatic pathology in a cohort of HCV-infected male veterans. We estimated and adjusted for daily intake of vitamin D from diet using a Dietary History Questionnaire, and dispensed prescriptions prior to study enrollment. We used race-stratified logistic regression analyses to evaluate the relationship between serum vitamin D levels and risk of advanced fibrosis (F3/F4-F4) and advanced inflammation (A2/A3-A3).
Results
A total of 163 African American (AA) and 126 White non-Hispanics were studied. Overall, ~44% of AAs and 15% of Whites were vitamin D deficient or insufficient (<20 ng/mL); 4% of AAs and 9% of Whites had an elevated level (>50 ng/mL). Among AAs, patients with elevated serum vitamin D levels had significantly higher odds of advanced fibrosis (OR=12.91, p=0.03) than those with normal levels. In contrast, AAs with insufficient or deficient levels had > two-fold excess risk of advanced inflammation (p=0.06). Among Whites, there was no association between vitamin D levels and advanced fibrosis (F3/F4-F4) or inflammation (A2/A3-A3) risk.
Conclusions
We observed potential differences in the association between vitamin D levels and degree of HCV-related hepatic fibrosis between White and AA males. Additional research is necessary to confirm that high serum vitamin D levels may be associated with advanced fibrosis risk in African American males, and to evaluate racial differences exist in HCV-infected females.
doi:10.1111/apt.12341
PMCID: PMC3742078  PMID: 23710689

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