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Drug-drug-interactions (DDIs) occur when a drug alters the metabolic rate, efficacy, and toxicity of concurrently used drugs. While almost 1 in 4 adults now use at least 3 concurrent prescription drugs in the United States, the Non-alcoholic fatty liver disease (NAFLD) prevalence has also risen over 25%. The effect of NALFD on DDIs is largely unknown. NAFLD is characterized by lipid vesicle accumulation in the liver, which can progress to severe steatohepatitis (NASH), fibrosis, cirrhosis, and hepatic carcinoma. The CYP450 enzyme family dysregulation in NAFLD, which might already alter the efficacy and toxicity of drugs, has been partially characterized. Nevertheless, the drug-induced dysregulation of CYP450 enzymes has not been studied in the fatty liver. These changes in enzymatic inducibility during NAFLD, when taking concurrent drugs, could cause unexpected fatalities through inadvertent DDIs. We have, thus, developed an in vitro model to investigate the CYP450 transcriptional regulation in NAFLD. Specifically, we cultured primary human hepatocytes in a medium containing free fatty acids, high glucose, and insulin for seven days. These cultures displayed intracellular macro-steatosis after 5 days and cytokine secretion resembling NAFLD patients. We further verified the model's dysregulation in the transcription of key CYP450 enzymes. We then exposed the NAFLD model to the drug inducers rifampicin, Omeprazole, and Phenytoin as activators of transcription factors pregnane X receptor (PXR), aryl hydrocarbon receptor (AHR) and constitutive androstane receptor (CAR), respectively. In the NAFLD model, Omeprazole maintained an expected induction of CYP1A1, however Phenytoin and Rifampicin showed elevated induction of CYP2B6 and CYP2C9 compared to healthy cultures. We, thus, conclude that the fatty liver could cause aggravated drug-drug interactions in NAFLD or NASH patients related to CYP2B6 and CYP2C9 enzymes. [Display omitted] • Human hepatocytes fattened by fatty acids show early signs of inflammation. • Expression of CYP450s is altered in fattened human hepatocytes. • Patients with fatty liver might experience altered drug toxicity and efficacy. • Inducibility of some CYP450s is altered in fattened human hepatocytes. • Patients with fatty liver might have a higher tendency for drug-drug interactions. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatitis C virus (HCV) is a prominent liver disease that often presents with mental illness. We stratify the HCV population and review its healthcare burden on the US hospital system., Methods: The US National Inpatient Sample was used to select admissions related to HCV between 2016 and 2019. Weights were assigned to discharges, and trend analyses were performed. Strata were formed across demographics, comorbidities, psychiatric and substance use conditions, and other variables. Outcomes of interest included hospitalization incidences, mortality rates, total costs, and mean per-hospitalization costs., Results: From 2016 to 2019, there were improvements in mortality and hospitalization incidence for HCV, as well as a decline in aggregate costs across the majority of strata. Exceptions that showed cost growth included admissions with multiple psychiatric, stimulant use, or poly-substance use disorders, and a history of homelessness. Admissions with no psychiatric comorbidities, admissions with no substance use comorbidities, and admissions with housing and without HIV comorbidity showed decreasing total costs. Along with per-capita mean costs, admissions with comorbid opioid use, bipolar, or anxiety disorder showed significant increases. No significant trends in per-capita costs were found in admissions without mental illness diagnoses., Conclusions: Most strata demonstrated decreases in hospitalization incidences and total costs surrounding HCV; however, HCV cases with mental illness diagnoses saw expenditure growth. Cost-saving mechanisms for these subgroups are warranted., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)