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 nonalcoholic 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

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 4β-hydroxycholesterol (4βHC) and 6β-hydroxycortisol (6βHCL) 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 (4βHC and 6βHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single-time-point oral midazolam (MDZ) phenotyping strategy. Plasma 4βHC and 6βHCL 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, 4βHC and 6βHCL 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 4βHC MR (p = 0.0003 and p = 0.032, respectively). Neither 4βHC nor 6βHCL MRs were associated with MDZ oral clearance. Plasma 4βHC and 6βHCL MRs do not relate to MDZ single-time-point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals

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

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 HbA RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD

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

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

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

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

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