Apixaban and Rosuvas--tatin Pharmacokinetics in Nonalcoholic Fatty Liver Disease.

There is little known about the impact of nonalcoholic fatty liver disease (NAFLD) on drug metabolism and transport. We examined the pharmacokinetics of oral apixaban (2.5 mg) and rosuvastatin (5 mg) when administered simultaneously in subjects with magnetic resonance imaging-confirmed NAFLD (N = 22) and healthy control subjects (N = 12). The area under the concentration-time curve to the last sampling time (AUC0-12) values for apixaban were not different between control and NAFLD subjects (671 and 545 ng/ml × hour, respectively; P = 0.15). Similarly, the AUC0-12 values for rosuvastatin did not differ between the control and NAFLD groups (25.4 and 20.1 ng/ml × hour, respectively; P = 0.28). Furthermore, hepatic fibrosis in NAFLD subjects was not associated with differences in apixaban or rosuvastatin pharmacokinetics. Decreased systemic exposures for both apixaban and rosuvastatin were associated with increased body weight (P < 0.001 and P < 0.05, respectively). In multivariable linear regression analyses, only participant weight but not NAFLD, age, or SLCO1B1/ABCG2/CYP3A5 genotypes, was associated with apixaban and rosuvastatin AUC0-12 (P < 0.001 and P = 0.06, respectively). NAFLD does not appear to affect the pharmacokinetics of apixaban or rosuvastatin.

A Fibroblast Growth Factor 21-Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expression in humans as well as mouse and human hepatoma models of the disease. Here, we investigated the role of the lipid- and glucose-modulating hormone fibroblast growth factor 21 (FGF21) in the molecular mechanism regulating CYP3A4 expression in NAFLD. In human subjects, mouse and cellular NAFLD models with lower CYP3A4 expression, circulating FGF21, or hepatic FGF21 mRNA levels were elevated. Administration of recombinant FGF21 or transient hepatic overexpression of FGF21 resulted in reduced liver CYP3A4 luciferase reporter activity in mice and decreased CYP3A4 mRNA expression and activity in cultured Huh7 hepatoma cells. Blocking canonical FGF21 signaling by pharmacological inhibition of MEK1 kinase in Huh7 cells caused de-repression of CYP3A4 mRNA expression with FGF21 treatment. Mice with high-fat diet-induced simple hepatic steatosis and lipid-loaded Huh7 cells had reduced nuclear localization of the pregnane X receptor (PXR), a key transcriptional regulator of CYP3A4 Furthermore, decreased nuclear PXR was observed in mouse liver and Huh7 cells after FGF21 treatment or FGF21 overexpression. Decreased PXR binding to the CYP3A4 proximal promoter was found in FGF21-treated Huh7 cells. An FGF21-PXR signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in NAFLD.

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world, given its association with obesity, type 2 diabetes, and dyslipidemia. Medications are widely used in NAFLD to manage comorbid conditions, and there is significant interest in developing new drug therapies to treat the disease. Despite this, little is known about the effects of NAFLD on drug metabolism. We examined the activity and expression of the major drug-metabolizing enzyme subfamily, CYP3A, in subjects with NAFLD as well as in mouse and cellular models. CYP3A activity was determined in healthy volunteers and subjects with biopsy-proven NAFLD by oral midazolam phenotyping and measurement of plasma 4ß-hydroxycholesterol, an endogenous metabolic biomarker. CYP3A4 transcriptional activity, metabolic activity, and expression were also assessed in a mouse and cellular model of NAFLD. Subjects with nonalcoholic steatohepatitis (NASH) had 2.4-fold higher plasma midazolam levels compared with controls. Plasma 4ß-hydroxycholesterol was 51% and 37% lower than controls in subjects with simple steatosis and NASH, respectively. Fibrosis was associated with 57% lower plasma 4ß-hydroxycholesterol levels than controls. Furthermore, hepatic CYP3A4 mRNA expression in NASH was 69% lower than control livers. CYP3A4 gene luciferase activity in the livers of NAFLD mice was 38% lower than that of controls. Lipid-loaded Huh7 human hepatoma cells had a 38% reduction in CYP3A4 activity and 80% lower CYP3A4 mRNA expression compared with the control. CYP3A activity is reduced in human NAFLD in addition to mouse and in vitro cell models of the disease.

Validation of volumetric and single-slice MRI adipose analysis using a novel fully automated segmentation method.

PURPOSE: To validate a fully automated adipose segmentation method with magnetic resonance imaging (MRI) fat fraction abdominal imaging. We hypothesized that this method is suitable for segmentation of subcutaneous adipose tissue (SAT) and intra-abdominal adipose tissue (IAAT) in a wide population range, easy to use, works with a variety of hardware setups, and is highly repeatable. MATERIALS AND METHODS: Analysis was performed comparing precision and analysis time of manual and automated segmentation of single-slice imaging, and volumetric imaging (78-88 slices). Volumetric and single-slice data were acquired in a variety of cohorts (body mass index [BMI] 15.6-41.76) including healthy adult volunteers, adolescent volunteers, and subjects with nonalcoholic fatty liver disease and lipodystrophies. A subset of healthy volunteers was analyzed for repeatability in the measurements. RESULTS: The fully automated segmentation was found to have excellent agreement with manual segmentation with no substantial bias across all study cohorts. Repeatability tests showed a mean coefficient of variation of 1.2 ± 0.6% for SAT, and 2.7 ± 2.2% for IAAT. Analysis with automated segmentation was rapid, requiring 2 seconds per slice compared with 8 minutes per slice with manual segmentation. CONCLUSION: We demonstrate the ability to accurately and rapidly segment regional adipose tissue using fat fraction maps across a wide population range, with varying hardware setups and acquisition methods.

Inflammation is not the cause of an elevated serum ferritin in non-alcoholic fatty liver disease.

BACKGROUND: In non-alcoholic fatty liver disease (NALFD), it has often been assumed that an elevation in serum ferritin is likely related to inflammation rather than iron overload. MATERIAL AND METHODS: Patients referred with NAFLD were entered into a clinical study of phlebotomy therapy. A liver biopsy with liver iron concentration was done at entry and 6 months after phlebotomy (n = 56) until the patient had a low serum ferritin or developed anemia. Serum ferritin was compared to liver iron concentration, ESR, CRP, BMI and grade of inflammation on liver biopsy. RESULTS: Iron removed by phlebotomy in NAFLD correlated with the decrease in serum ferritin (r = 0.57, p = 0.0014) and liver iron concentration (r = 0.57, p = 0.0013). There was no significant correlations between serum ferritin and ESR, CRP or grade of liver inflammation. CONCLUSIONS: Serum ferritin is related to liver iron storage in NAFLD and decreasing body iron stores by phlebotomy is reflected by an appropriate decrease in serum ferritin. Inflammation is not the cause of the elevated serum ferritin in fatty liver disease.

Current treatment options for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease is the leading cause of liver disease in western society. It is a cause of end-stage liver disease, with increased mortality secondary to cirrhosis and its complications. It is also recognized that cardiovascular disease is a significant cause of death in these patients. Significant work evaluating various treatments has been performed in recent years; however, to date, no ideal therapy exists. Lifestyle modification remains the cornerstone of management. The present article reviews the current status of various treatment modalities evaluated in nonalcoholic fatty liver disease.

Treatment of hyperferritinemia.

Elevated serum ferritin, or hyperferritinemia, is a common finding on routine bloodwork and often prompts referral for further evaluation. In the following review, we outline the various causes of hyperferritinemia and point out that, in the majority of cases, this does not represent true iron overload. Despite much research interest in this area, the precise mechanism of hyperferritinemia and its impact on disease severity in various clinical conditions continues to be debated. While some research suggests that iron reduction in cases of hyperferritinemia is of benefit, the decision to treat such patients should be individualized, and may be influenced by the presence of other features of iron overload.

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA1c and continuous glucose monitoring over 12 months. RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, N = 1,298] vs. 4.7% [95% CI 3.4-5.9%, N = 1,089], P = 0.035) with lower rates of prior CD screening (6.9% vs. 44.2%, P < 0.0001). Fifty-one participants were randomized to a GFD (N = 27) or GCD (N = 24). No HbA1c differences were seen between the groups (+0.14%, 1.5 mmol/mol; 95% CI -0.79 to 1.08; P = 0.76), although greater postprandial glucose increases (4-h +1.5 mmol/L; 95% CI 0.4-2.7; P = 0.014) emerged with a GFD. CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD.

Equity and Gender Issues Among Members of the Canadian Association of Gastroenterology.

BACKGROUND: Gender equity has historically been a challenge within gastroenterology. AIMS: The Canadian Association of Gastroenterology (CAG) developed a survey to identify issues pertaining to equity and gender faced by its membership and to determine areas of action. METHODS: In 2014, the survey was emailed to all 1155 CAG members, and the data were analyzed using statistical methods. RESULTS: One hundred eleven CAG members responded to the survey. Of those, 52% were male, 75% were between 26 and 45 years of age, and 55% were in their first decade of practice. More males held the status of full professor (21% versus 0%; P=0.022). Male CAG members reported working more hours per week than their female counterparts (58.3 ± 15.4 versus 52.3 ± 11.8, P=0.025). Regarding commitments outside the workplace, 81% of respondents had a spouse/partner, and 52% had children under 18 years of age, both of which did not significantly differ based on gender. Overall, 70% were satisfied or very satisfied with their career path. However, significantly more females felt their age/ethnicity/gender/marital status hindered career advancement (36% versus 14%; P=0.008). Furthermore, more females reported difficulties attaining work-life balance (45% versus 22%; P=0.015). CONCLUSIONS: This survey highlights that gender and equity challenges continue to exist within gastroenterology. The needs assessment highlights that work-life balance, physician well-being, negotiation skills and mentorship are areas of importance to many CAG members.

Colonic interposition in a woman with attenuated familial adenomatosis polyposis: does the location of the colon affect polyp formation?

Attenuated familial adenomatous polyposis (AFAP) is a rare but well-established cause of colorectal carcinoma and multiple polyps. The present paper describes a case of a woman diagnosed with colorectal cancer at 34 years of age and subsequently found to have AFAP by genetic testing. During infancy, the patient underwent surgical correction of esophageal atresia with colonic interposition. While she had developed adenomatous polyps in her native cecum, there was no evidence of polyps or cancer in the segment of large intestine interposed between her upper esophagus and stomach. Therefore, various environmental differences between the upper and lower gastrointestinal tract may play a role in the expression of AFAP phenotype.

The myths and realities of hemochromatosis.

Hemochromatosis is a common genetic condition and yet there are still a number of misperceptions surrounding the diagnosis and management of this condition. Hemochromatosis affects both men and women. Typical patients do not have alcoholism or viral hepatitis, and often have normal liver enzymes. Clinical expression is highly variable. Genetic testing is widely available and particularly useful in family studies. Hemochromatosis can be readily diagnosed and treated. The purpose of the present review is to address the medical myths and misconceptions of hemochromatosis.

Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial.

AIM: To evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH). METHODS: Twelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy. RESULTS: Sitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 µg/mL vs 3.9 ± 2.7 µg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 µg/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002. CONCLUSION: Sitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.

Prognostic factors and survival in patients with hereditary hemochromatosis and cirrhosis.

OBJECTIVES: The survival of treated, noncirrhotic patients with hereditary hemochromatosis is similar to that of the general population. Less is known about the outcome of cirrhotic hereditary hemochromatosis patients. The present study evaluated the survival of patients with hereditary hemochromatosis and cirrhosis. METHODS: From an established hereditary hemochromatosis database, all cirrhotic patients diagnosed from January 1972 to August 2004 were identified. Factors associated with survival were determined using univariate and multivariate regression. Survival differences were assessed using the Kaplan-Meier life table method. RESULTS: Ninety-five patients were identified. Sixty patients had genetic testing, 52 patients (87%) were C282Y homozygotes. Median follow-up was 9.2 years (range 0 to 30 years). Nineteen patients (20%) developed hepatocellular carcinoma, one of whom was still living following transplantation. Cumulative survival for all patients was 88% at one year, 69% at five years and 56% at 20 years. Factors associated with death on multivariate analysis included advanced Child-Pugh score and hepatocellular carcinoma. Patients with hepatocellular carcinoma were older at the time of diagnosis of cirrhosis (mean age 61 and 54.6 years, respectively; P=0.03). The mean age at the time of diagnosis of hepatocellular carcinoma was 70 years (range 48 to 79 years). No other differences were found between the groups. CONCLUSIONS: Patients with hereditary hemochromatosis and cirrhosis are at significant risk of developing hepatocellular carcinoma. These patients are older when diagnosed with carcinoma and may have poorer survival following transplantation than patients with other causes of liver disease. Early diagnosis and treatment of hereditary hemochromatosis by preventing the development of cirrhosis may reduce the incidence of hepatocellular carcinoma in the future.

Relationships between Endogenous Plasma Biomarkers of Constitutive Cytochrome P450 3A Activity and Single-Time-Point Oral Midazolam Microdose Phenotype in Healthy Subjects.

Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug phenotyping strategies, as well as endogenous biomarkers for assessment of in vivo CYP3A activity. The biomarkers 4ß-hydroxycholesterol (4ßHC) and 6ß-hydroxycortisol (6ßHCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4ßHC and 6ßHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single-time-point oral midazolam (MDZ) phenotyping strategy. Plasma 4ßHC and 6ßHCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral MDZ microdose (100 µg). Simple linear and multiple linear regression analyses were performed to assess relationships between MDZ oral clearance, biomarkers and subject covariates. Among study subjects, basal MDZ oral clearance, 4ßHC and 6ßHCL MRs ranged 6.5-, 10- and 13-fold, respectively. Participant age and alcohol consumption were negatively associated with MDZ oral clearance (p = 0.03 and p = 0.045, respectively), while weight and female sex were associated with lower plasma 4ßHC MR (p = 0.0003 and p = 0.032, respectively). Neither 4ßHC nor 6ßHCL MRs were associated with MDZ oral clearance. Plasma 4ßHC and 6ßHCL MRs do not relate to MDZ single-time-point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals.

Management of non-alcoholic fatty liver disease in 2015.

There is no single pharmacologic therapy that has been approved to treat nonalcoholic fatty liver disease in the general population. The backbone of therapy currently includes intensive lifestyle modification with established targets for diet and weight loss. The use of unsweetened, unfiltered coffee along with limiting high fructose corn syrup have emerged as beneficial dietary recommendations. The use of empiric oral hypoglycemic agents and vitamin E, however, has not been widely accepted. Developing bariatric surgical techniques are promising, but additional studies with long-term follow up are needed before it can be widely recommended. Finally, liver transplantation is an increasingly frequent consideration once complications of end-stage disease have developed. The future treatment of those with nonalcoholic fatty liver disease will likely involve a personalized approach. The importance of the gut microbiome in mediating hepatocyte inflammation and intestinal permeability is emerging and may offer avenues for novel treatment. The study of anti-fibrotic agents such as pentoxifylline and FXR agonists hold promise and new pathways, such as hepatocyte cannabinoid receptor antagonists are being studied. With the incidence of obesity and the metabolic syndrome increasing throughout the developed world, the future will continue to focus on finding novel agents and new applications of existing therapies to help prevent and to mediate the progression of nonalcoholic fatty liver disease.

The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) protocol: a randomised controlled study to evaluate treatment of asymptomatic coeliac disease in type 1 diabetes.

INTRODUCTION: Coeliac disease (CD) is an autoimmune condition characterised by gluten-induced intestinal inflammation, and observed at a 5-10 fold greater prevalence in type 1 diabetes. While universal screening for CD in patients with diabetes is frequently advocated, objective data is limited as to benefits on diabetes control, bone health or quality of life related to the adoption of a gluten-free diet (GFD) in the large proportion of patients with diabetes with asymptomatic CD. The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) study is a multicenter, randomised controlled trial to evaluate the efficacy and safety of a GFD in patients with type 1 diabetes with asymptomatic CD. METHODS AND ANALYSIS: Children and adults (8-45 years) with type 1 diabetes will be screened for asymptomatic CD. Eligible patients with biopsy-proven CD will be randomly assigned in a 1:1 ratio to treatment with a GFD for 1 year, or continue with a gluten-containing diet. The primary outcome will evaluate the impact of the GFD on change in glycated haemoglobin. Secondary outcomes will evaluate changes in bone mineral density, blood glucose variability and health-related quality of life between GFD-treated and the regular diet group over a 1-year period. The study was initiated in 2012 and has subsequently expanded to multiple paediatric and adult centres in Ontario, Canada. ETHICS AND DISSEMINATION: The findings from this study will provide high-quality evidence as to the impact of GFD treatment on glycaemic control and complications in asymptomatic children and adults with CD and type 1 diabetes. TRIAL REGISTRATION NUMBER: NCT01566110.