Antifibrotic and molecular aspects of rifaximin in alcoholic liver disease: study protocol for a randomized controlled trial

Abstract Background Alcoholic liver disease is the leading cause of cirrhosis worldwide. Due to an increase in alcohol overuse, alcoholic liver disease has become an increased burden on health care systems. Abstinence from alcohol remains the cornerstone of alcoholic liver disease treatment; however, this approach is hampered by frequent relapse and lack of specific therapy for treating advanced cases of liver disease. In the present study, we hypothesized that gut microbiota drive the development of liver fibrosis and that modulation of gut microbiota with the gut-selective, nonabsorbable antibiotic rifaximin attenuates alcoholic liver fibrosis. Methods/design Our double-blind, placebo-controlled trial will include 136 participants with biopsy-verified alcoholic fibrosis (Ishak liver fibrosis score of 1–4). Participants are randomized 1:1 to receive placebo or 550 mg of rifaximin twice daily for 18 months. A liver biopsy will be performed at the end of the treatment period to evaluate the effect of drug treatment on liver fibrosis. Stool, urine, and saliva specimens will be collected before treatment begins, at 1 month, and at the end of the treatment period. Fecal samples are used for microbiome deep sequencing. Changes in microbiome composition are compared before and after the trial medication period and linked to changes in liver fibrosis. Discussion This is the first clinical trial to evaluate the effect of gut microbiota on liver fibrosis in humans. If gut microbiota are an important promoter of alcoholic liver disease, current results may open new therapeutic avenues and revolutionize the current understanding of chronic liver diseases. Trial registration EudraCT, 2014–001856-51. Registered on 16 August 2014

High risk of misinterpreting liver and spleen stiffness using 2D shear-wave and transient elastography after a moderate or high calorie meal.

Food intake increases liver stiffness, but it is believed that liver stiffness returns to baseline two hours after a meal. The aim of this study was to investigate the impact of different sized meals on liver stiffness. Liver and spleen stiffness was measured with transient elastography (TE) and real-time 2-dimensional shear wave elastography (2D-SWE). Patients ingested a 625 kcal and a 1250 kcal liquid meal on two consecutive days. We measured liver and spleen elasticity, Controlled attenuation parameter (CAP) and portal flow at baseline and after 20, 40, 60, 120 and 180 minutes. Sixty patients participated, 83% with alcoholic liver disease. Twenty-eight patients had METAVIR fibrosis score F0-3 and 32 patients had cirrhosis. Liver stiffness, spleen stiffness and CAP increased after both meals for all stages of fibrosis. False positive 2D-SWE liver stiffness measurements caused 36% and 52% of patients with F0-3 fibrosis to be misclassified with higher stages of fibrosis after the moderate and high caloric meal. Likewise, 10% and 13% of compensated cirrhosis patients were misclassified with clinically significant portal hypertension after the two meals. We observed similar misclassification rates with TE. After three hours, liver stiffness remained elevated more than 20% from baseline in up to 50% of patients. IN CONCLUSION:Liver stiffness, spleen stiffness and CAP increase after a meal across all stages of fibrosis and across elastography techniques. Up to half of patients may be misclassified with higher stages of fibrosis, if they are assessed after less than three hours fasting period

Controlled Attenuation Parameter (CAP) for the assessment of alcoholic hepatic steatosis:biopsy-controlled diagnostic accuracy and role of detoxification

This book concerns the foundations of epistemic modality. I examine the nature of epistemic modality, when the modal operator is interpreted as concerning both apriority and conceivability, as well as states of knowledge and belief. The book demonstrates how epistemic modality relates to the computational theory of mind; metaphysical modality; deontic modality; the types of mathematical modality; to the epistemic status of undecidable propositions and abstraction principles in the philosophy of mathematics; to the apriori-aposteriori distinction; to the modal profile of rational propositional intuition; and to the types of intention, when the latter is interpreted as a modal mental state. Each essay is informed by either epistemic logic, modal and cylindric algebra or coalgebra, intensional semantics or hyperintensional semantics. The book's original contributions include theories of: (i) epistemic modal algebras and coalgebras; (ii) cognitivism about epistemic modality; (iii) two-dimensional truthmaker semantics, and interpretations thereof; (iv) the ground-theoretic ontology of consciousness; (v) fixed-points in vagueness; (vi) the modal foundations of mathematical platonism; (vii) a solution to the Julius Caesar problem based on metaphysical definitions availing of notions of ground and essence; (viii) the application of epistemic two-dimensional semantics to the epistemology of mathematics; and (ix) a modal logic for rational intuition. I develop, further, a novel approach to conditions of self-knowledge in the setting of the modal $\mu$-calculus, as well as novel epistemicist solutions to Curry's and the liar paradoxes. Solutions to previously intransigent issues concerning the first-person concept, the distinction between fundamental and derivative truths, and the unity of intention and its role in decision theory, are developed along the way