Carol Hawkins

Double blind randomized placebo controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis

Background: Nonalcoholic steatohepatitis (NASH) is common and severe in patients with diabetes mellitus. Although, there are no effective treatments for NASH in diabetic patients, preliminary reports suggest that polyunsaturated fatty acids (PUFA) may be beneficial in these patients. Aim: A prospective, randomized, double-blind placebo-controlled study (NCT 00323414) was performed in NASH patients with diabetes. Clinicaltrials.gov (NCT 00323414). Subjects and Methods: A total of 37 patients (50.6±9.8 y) with well-controlled diabetes (HbA1C<8.5%) were randomized to receive either PUFA containing eicosapentaenoic acid (2160 mg) and docosahexaenoic acid (1440 mg) daily or an isocaloric, identical placebo containing corn oil for 48 weeks under CONSORT guidelines. Clinical, demographics, biochemical laboratory tests, body composition using DEXA, and liver biopsy were performed at randomization and at the end of treatment. Liver biopsy was scored by the NASH CRN criteria. An intention-to-treat analysis was performed. Results: At inclusion, sex, age, body weight, biochemical tests, glucose control, and liver histology were similar in the 2 treatment groups. There was no change in liver enzymes, body weight, or body composition during the study in either group. At the end of the treatment, hepatic steatosis and the activity score improved (P<0.05) and lobular inflammation worsened (P<0.001) with placebo but was unchanged with PUFA. At the end of the treatment, insulin resistance (serum glucose and HOMA) worsened with PUFA but not placebo. Conclusions: PUFA provided no benefit over placebo in NASH patients with diabetes. The effects of PUFA on histology and insulin resistance were inferior to placebo. These data provide no support for PUFA supplements in NASH.

Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non alcoholic fatty liver disease

Hypovitaminosis D is common in obesity and insulin‐resistant states. Increased fat mass in patients with non‐alcoholic fatty liver disease (NAFLD) may contribute to hypovitaminosis D. To determine the relation among plasma vitamin D concentration, severity of disease and body composition in NAFLD.

Renin‐angiotensin system and fibrosis in non‐alcoholic fatty liver disease

Therapeutic options are limited for patients with non‐alcoholic fatty liver disease (NAFLD). One promising approach is the attenuation of necroinflammation and fibrosis by inhibition of the renin‐angiotensin system (RAS). We explored whether the risk of fibrosis was associated with the use of commonly used medications in NAFLD patients with hypertension. Specifically, we sought to determine the association between RAS blocking agents and severity of hepatic fibrosis in NAFLD patients with hypertension.

Clinical spectrum of non-alcoholic fatty liver disease in diabetic and non-diabetic patients

Background While non-alcoholic fatty liver disease (NAFLD) has been well characterised in patients with diabetes mellitus (DM), less is known about NAFLD in non-DM patients. We investigated the clinical characteristics of NAFLD patients with and without DM and accuracy of the NAFLD fibrosis score (NFS) in these two NAFLD groups. Methods Clinical, biochemical and histological variables were evaluated in this prospective cross-sectional study of 503 patients with biopsy proven NAFLD. Comparisons between patients with and without DM were analysed. NFS was correlated with liver histology to assess its robustness in patients with and without DM. Results There were 503 biopsy proven NAFLD patients with 48% of the cohort being diabetic. Relative to patients without DM, patients with DM were older (52 vs. 46 years, p < 0.001), with higher proportion of females (70% vs. 54%, p < 0.001), higher BMI (37 vs. 35, p = 0.009), higher prevalence of hypertension (73% vs. 44%, p < 0.001), higher prevalence of NASH (80.2% vs. 64.4%; p < 0.001) and advanced fibrosis (40.3% vs. 17.0%; p < 0.001). A considerable amount of patients without DM still had NASH (64%) and advanced fibrosis (17%). The clinical utility of the NFS differed between NAFLD patients with and without DM, with sensitivity to exclude advanced fibrosis being 90% of NAFLD patients with DM but only 58% of patients without DM. Conclusion Patients with DM have more severe NAFLD based on histology. However, NASH and advanced fibrosis also occur in a considerable proportion of NAFLD patients without DM. The lower utility of the NFS in NAFLD patients without DM emphasises the heterogeneous nature of the NAFLD phenotype.

Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis

BACKGROUND & AIMS: Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. METHODS: We collected data from 3 large U.S. studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. RESULTS: Premenopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory‐Denk bodies than men and also at an increased risk of lobular inflammation and Mallory‐Denk bodies than postmenopausal women (P < .01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory‐Denk bodies in premenopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in postmenopausal women (P < .05). CONCLUSIONS: Being a premenopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress.

The development of a non-invasive model to predict the presence of non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease.

Non‐alcoholic steatohepatitis (NASH) is an advanced and aggressive form of non‐alcoholic fatty liver disease (NAFLD), which remains difficult to diagnose without a liver biopsy. Hyperferritinemia has increasingly been associated with the presence of NASH. Hence, we sought to explore the relationship between ferritin and NASH and to develop a composite model based on ferritin to predict the presence of NASH.

Diabetes Mellitus, Insulin, Sulfonylurea and Advanced Fibrosis in Non- Alcoholic Fatty Liver Disease

Background & aims: Diabetes mellitus is a risk factor for advanced fibrosis in non-alcoholic fatty liver disease. However, not all non-alcoholic fatty liver disease patients with diabetes develop advanced fibrosis. We hypothesised that prescription medications used by these patients influence the development of advanced fibrosis. We investigated the association of commonly used medications and advanced fibrosis in non-alcoholic fatty liver disease patients with diabetes. Methods: Clinical information including demographics, medical history, medication history, biochemical and histologic variables were ascertained in 459 patients with biopsy proven non-alcoholic fatty liver disease. We compared characteristics of patients with and without diabetes and explored potential associations between classes of drugs as risk factors and advanced fibrosis among the diabetic patients with NAFLD. Results: Presence of diabetes was an independent risk factor for advanced fibrosis. In diabetic patients, age (OR 1.09; 95%CI 1.04-1.15, p=0.000) and grade of ballooning (OR 5.59; 95%CI 2.69-11.61, p=0.000) had a positive relationship with advanced fibrosis. The use of insulin (OR 4.95; 95%CI 1.65-14.88, p=0.004) and sulfonylurea (OR 5.07; 95%CI 1.87-13.75, p=0.001) were positively associated while statin use (OR 0.31; 95%CI 0.12-0.78, p=0.013) was negatively associated with advanced fibrosis. Conclusion: Among non-alcoholic fatty liver disease patients with diabetes, the prevalence of advanced fibrosis was higher in patients treated with insulin and sulfonylurea, but lower in patients on statins. These findings provide support for a greater role of statin use in non-alcoholic fatty liver disease patients with diabetes while limiting the use of insulin and sulfonylurea.

Response to: Laboratory assessment may be dependent on the time of liver biopsy

To the Editor: We thank Kayadibi, Sertoglu and Uyanik for their interest in our study and their thoughtful comments. The cross sectional study analyses were conducted to test our hypothesis that concomitant medications used by patients with NAFLD may be associated with advanced fibrosis based on our observations at liver clinics with patients seeking medical advice for multiorgan and multiple system affecting conditions or comorbidities. We agree with Kayadibi and colleagues that a more rigorous prospective experimental design to test similar hypotheses would be beneficial. However, we also think that existing electronic medical records, as utilized in our study, provide a unique opportunity for hypotheses testing for preliminary ground work for more definitive longitudinal studies. In the present study, patients were followed up as part of prospective studies and the electronic data were verified during subsequent visits allowing us to be confident about the fidelity of the data. Nonetheless, the study findings should be interpreted with consideration of the limitations of a cross-sectional study, as discussed in our paper. Kayadibi and colleagues describe a common statistical practice of using univariate logistic regression analysis as a screening tool to identify potential independent risk factors before evaluation with multivariate analysis with a cautionary note of proper diagnostics that is well received. While we agree with these analytical principles and comply with generally accepted methodology in our work, we would like to share our view that this may specifically help to generate possible hypotheses along the way. However, this practice may not be suitable for all studies, especially if a theory or hypothesis is already being considered. We conducted the study to test our hypothesis that concomitant medications such as RAS-B (Rennin Angiotensin System Blockers) may be associated with fibrogenesis in NAFLD patients. The multivariate analysis was performed specifically evaluating the relationship between pre-existing medication and advanced fibrosis and also adjusted for other relevant risk factors of advanced fibrosis when clinical and laboratory data were available through existing electronic medical records. The second point to be addressed is the timing of the laboratory assessment with regards to the liver biopsy. We thank Kayadibi and colleagues for commenting on this important source of biological variability in humans and fully acknowledge that biochemical parameters present dynamic challenges in relation to liver biopsy outcomes. In response, we would like to emphasize the setting of our study where several patients attended liver clinics as referrals and repeated laboratory measures were not justified in many circumstances which led to our inclusion of available clinical data without temporal specification. Having said that, the majority of our patients had laboratory tests performed within 90 days of their liver biopsies. Nevertheless, the considerations raised by Kayadibi and colleagues are useful to reflect upon and to refine the methodology for any further prospective longitudinal studies of RAS-B in patients with NAFLD.