The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol-associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH-cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH. (Hepatology Communications 2021;0:1-24).

AIMTo assess the effect of sofosbuvir (SOF) based regimens on glycemic and lipid control.METHODSThis is a retrospective analysis of hepatitis C virus (HCV)-infected patients treated and cured with a SOF regimen [SOF/ribavirin/interferon, SOF/simeprevir, or SOF/ledipasvir (LDV) ± ribavirin] from January 2014 to March 2015. Patients with hemoglobin A1C (HbA1C) and lipid panels within six months before and six months after therapy were identified and included in our study. Due to the known hemolytic effect of ribavirin, HbA1C was obtained a minimum of three months post-treatment for the patients treated with a ribavirin regimen. Medical history, demographics, HCV genotype, pre-therapy RNA, and liver biopsies were included in our analysis. The patients who started a new medication or had an adjustment of baseline medical management for hyperlipidemia or diabetes mellitus (DM) were excluded from our analysis.RESULTSTwo hundred and thirty-four patients were reviewed, of which 60 patients met inclusion criteria. Sixty-three point three percent were male, 26.7% were Caucasian, 41.7% were African American and 91.7% were infected with hepatitis C genotype 1. Mean age was 60.6 ± 6.7 years. Thirty-nine patients had HbA1C checked before and after treatment, of which 22 had the diagnosis of DM type 2. HbA1C significantly decreased with treatment of HCV (pretreatment 6.66% ± 0.95% vs post-treatment 6.14% ± 0.65%, P < 0.005). Those treated with SOF/LDV had a lower HbA1C response than those treated with other regimens (0.26% ± 0.53% vs 0.71% ± 0.83%, P = 0.070). Fifty-two patients had pre- and post-treatment lipid panels; there was a significant increase in low-density lipoprotein (LDL) and total cholesterol (TC) after treatment (LDL: 99.5 ± 28.9 mg/dL vs 128.3 ± 34.9 mg/dL, P < 0.001; TC: 171.6 ± 32.5 mg/dL vs 199.7 ± 40.0 mg/dL, P < 0.001). Pre-treatment body-mass index (BMI) did not differ from post-treatment BMI (P = 0.684).CONCLUSIONEradication of HCV with a SOF regimen resulted in a significant drop in HbA1C and an increase in LDL and TC post therapy.

SUMMARY BackgroundIt has been recognised that unconjugated bilirubin contains hepatic anti-fibrogenic and anti-inflammatory properties and is a potent physiological antioxidant cytoprotectant. We believe that unconjugated hyperbilirubinemia may protect against development of non-alcoholic steatohepatitis (NASH).

Patients with end-stage renal diseases on hemodialysis have a high prevalence of hepatitis C infection (HCV). In most patients, treatment for HCV is delayed until postrenal transplant. We assessed the effectiveness and tolerance of ledipasvir/sofosbuvir (LDV/SOF) in 32 postkidney transplant patients infected with HCV. The group was composed predominantly of treatment-naïve (75%) African American (68.75%) males (75%) infected with genotype 1a (62.5%). Most patients received a deceased donor kidney graft (78.1%). A 96% sustained viral response (SVR) was reported (27/28 patients). One patient relapsed. One patient with baseline graft dysfunction developed borderline rejection. No graft loss was reported. Six HIV-coinfected patients were included in our analysis. Five of these patients achieved SVR 12. There were four deaths, and one of the deaths was in the HIV group. None of the deaths were attributed to therapy. Coinfected patients tolerated therapy well with no serious adverse events. Serum creatinine remained stable at baseline, end of therapy, and last follow-up, (1.351±.50 mg/dL; 1.406±.63 mg/dL; 1.290±.39 mg/dL, respectively). In postkidney transplant patients with HCV infection with or without coinfection with HIV, a combination of LDV/SOF was well tolerated and effective.