Drug-induced liver injury in a chronic hepatitis C patient treated by peginterferon, ribavirin and simeprevir.

A 56-year-old male patient with chronic hepatitis C was treated with pegylated interferon (PEG IFN)-α-2b and ribavirin (RBV) for 72 weeks in 2006. The patient achieved an early virological response (EVR); however, hepatitis C relapsed 12 weeks after discontinuation of PEG IFN and RBV. In 2012, the patient was treated with a PEG IFN/RBV/telaprevir combination therapy. After 5 days of treatment, he suffered from a telaprevir-associated skin rash on his body and four limbs. He chose to be treated with PEG IFN and RBV until 60 weeks. He again achieved EVR but no sustained virological response. In 2014, he was treated with PEG IFN/RBV/simeprevir combination therapy. He achieved rapid virological response, but after 6 weeks of therapy, a striking elevation of serum aminotransferase level was recorded with no accompanying skin rash; he was admitted to our hospital. PEG IFN/RBV/simeprevir was stopped, but sodium valproate (400 mg/day), which had been administrated for more than 10 years to prevent epilepsy was continued. Liver biopsy revealed typical features of drug-induced liver injury. After stopping PEG IFN/RBV/simeprevir, serum aminotransferase levels soon returned to the normal range. We diagnosed this case to be simeprevir-induced hepatitis clinically and histologically. Physicians need to stay alert to the possibility of drug-induced liver injury in using simeprevir.

Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats.

BACKGROUND/AIMS: Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibit endogenous cholesterol synthesis, possess pleiotropic activities, such as anti-inflammatory, anti-oxidative and antifibrotic effects. Here, we investigated whether statins ameliorate steatohepatitis using a high-fat and high-cholesterol (HFHC) diet-induced rat model. METHODS: Eight-week-old male Sprague-Dawley rats were fed control chow or HFHC diet. Half of the HFHC diet-fed rats were orally administered 2 mg/kg/day rosuvastatin for 12 weeks. Hepatic injury, steatosis, fibrosis and markers of lipid peroxidation/oxidant stress were evaluated. RESULTS: As previously reported, HFHC diet induced steatohepatitis in rat livers with hypercholesterolaemia. Rosuvastatin decreased Oil Red O stained-positive areas, liver/body weight ratio, serum total cholesterol levels and hepatic free fatty acid contents in HFHC diet-fed rats. Further study revealed that rosuvastatin significantly decreased hepatic mRNA expression of tumour necrosis factor-α and interleukin-6, serum alanine aminotransferase levels and hepatic lobular inflammation grade. Hepatic fibrosis was also ameliorated by rosuvastatin with decreases in hepatic mRNA expression of transforming growth factor-ß, connective tissue growth factor and type-1 procollagen. Similarly, hepatic Sirius red stained or α-smooth muscle actin stained-positive areas and expression of markers of lipid peroxidation/oxidant stress [hepatic 8-hydroxy-oxyguanosine and hepatic 4-hydroxy-2-nonenal] were decreased. Interestingly, whereas the expression of carnitine palmitoyltransferase-1 and long-chain acyl-CoA dehydrogenase was not affected, that of catalase and acyl-coA oxidase was restored. CONCLUSIONS: These data suggest that rosuvastatin improved not only hepatic steatosis but also hepatic injury and fibrosis via improved peroxisomal ß-oxidation in this rat HFHC model.

In vivo expression patterns of survivin and its splicing variants in chronic liver disease and hepatocellular carcinoma.

AIM: Our aim was to clarify the significance of expression levels and post-transcriptional splicing patterns of survivin during multistep hepatocarcinogenesis and tumor progression. METHODS: Using immunohistochemistry, we first elucidated the expression of survivin protein in tissues of hepatocellular carcinoma (HCC) and the adjacent non-cancerous tissues. Furthermore, we investigated survivin gene expression patterns in these tissues. RESULTS: Survivin protein was expressed not only in most HCC tissues but also in some cirrhotic nodules. In non-cancerous regions, the levels of survivin mRNA increased in proportion to their stage of progression. Survivin protein was expressed mainly in periportal areas, where proliferating cells were localized. In HCC, mRNA levels of survivin and survivin Delta Ex3 correlated with high proliferative activity, whereas the levels of surviving 2B did not. DISCUSSION: These findings of mRNA and protein expressions of survivin in chronically injured avers indicate that it has an important role in hepatocarcinogenesis. A lack of correlation between proliferative activity and survivin 2B mRNA levels in HCC is suggestive of a previous hypothesis that this variant decreases sruvivin function in a dominant negative manner. Thus, our data suggest different functions of these splicing variants and their important roles in tumor progression.