Can negligible hepatic steatosis determined by magnetic resonance imaging-proton density fat fraction obviate the need for liver biopsy in potential liver donors?

The purpose of this study is to determine whether magnetic resonance (MR)-proton density fat fraction (PDFF) estimate of negligible hepatic fat percentage (<5%) can exclude significant hepatic steatosis (≥10%) in living liver donor candidates obviating the need for liver biopsy and to perform intraindividual comparisons between MR-PDFF techniques for hepatic steatosis quantification. In an ethics-approved retrospective study, 144 liver donor candidates with magnetic resonance spectroscopy (MRS) and 6-echo Dixon magnetic resonance imaging (MRI) between 2013 and 2015 were included. A subset of 32 candidates underwent liver biopsy. Hepatic fat percentage was determined using MR-PDFF and histopathology-determined fat fraction as the reference standard. A receiver operating characteristic analysis with positive predictive value, negative predictive value (NPV), sensitivity, and specificity was performed to discriminate between clinically significant steatosis (≥10%) or not (<10%) at MRS-PDFF and MRI-PDFF thresholds of 5% and 10%. Pearson correlation and Bland-Altman analyses between MRS-PDFF and MRI-PDFF were performed for intraindividual comparison of hepatic steatosis estimation. There was significant association between MRS-PDFF and MRI-PDFF with HP-FP. High NPV of 95% (95% confidence interval [CI], 78%-99%) and 100% (95% CI, 76%-100%) as well as an area under the curve of 0.90 (95% CI, 0.79-1.0) and 0.93 (95% CI, 0.84-1.0) were obtained with a cutoff threshold of 5% MRI-PDFF and MRS-PDFF, respectively, to exclude clinically significant steatosis (≥10%). Intraindividual comparison between MRS-PDFF and MRI-PDFF showed a Pearson correlation coefficient of 0.83. Bland-Altman analysis showed a mean difference of 1% with 95% limits of agreement between -1% and 3%. MR-PDFF estimate of negligible hepatic fat percentage (<5%) has sufficient NPV for excluding clinically significant hepatic steatosis (≥10%) in living liver donor candidates obviating the need for liver biopsy. It may be sufficient to acquire only the multiecho Dixon MRI-PDFF for hepatic steatosis estimation. Liver Transplantation 24 470-477 2018 AASLD.

Seizure susceptibility alteration following reversible cholestasis in mice: Modulation by opioids and nitric oxide.

There is an increasing body of evidence that the central nervous system is affected by cholestatic liver disorders. Cholestasis has been shown to result in a decreased seizure propensity which is believed to be mediated by an increased opioidergic tone and nitric oxide (NO) signaling pathway. In this study, we used a reversible chemically-induced cholestasis model in mice to investigate the changes in seizure susceptibility. The cholestasis was induced by intragastric administration of alpha-naphthylisothiocyanate (ANIT) (100 mg/kg) or vehicle (corn oil). The threshold to generalized clonic seizures induced by timed intravenous infusion of pentylenetetrazole (PTZ) was used as an index of seizure propensity. The role of opioid receptors and NO pathway in the changes of seizure threshold, and the responsiveness to the anticonvulsant effect of opioid agonist, morphine, during and after the resolution of cholestasis was studied in this reversible paradigm of cholestatic disease. A significant increase in cholestasis-related biochemical markers as well as in clonic seizure threshold was observed; it was maximal at day 3 after cholestasis induction and slowly decreased to normal thereafter. Seizure threshold rise was inhibited by chronic administration of the opioid antagonist naltrexone or acute administration of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO production. Co-administration of subeffective doses of L-NAME and naltrexone showed an additive effect. Injection of an anticonvulsant dose of morphine on day 7 after cholestasis induction did not increase seizure threshold, suggestive of a downregulation of receptors even after cholestasis resolution. These data shows that ANIT-induced cholestasis leads to a reversible increased resistance to PTZ-induced seizures through an opioid/NO-mediated pathway, and is probably accompanied by downregulation of opioid receptors.