ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistance-associated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation.
Subject(s)
Acetaminophen/pharmacokinetics , Analgesics, Non-Narcotic/pharmacokinetics , Liver/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Up-Regulation , Acetaminophen/analogs & derivatives , Acetaminophen/blood , Acetaminophen/urine , Adolescent , Analgesics, Non-Narcotic/blood , Analgesics, Non-Narcotic/urine , Bile Canaliculi/metabolism , Bile Canaliculi/pathology , Biotransformation , Child , Cohort Studies , Fatty Liver/blood , Fatty Liver/metabolism , Fatty Liver/pathology , Fatty Liver/urine , Female , Humans , Liver/pathology , Male , Multidrug Resistance-Associated Protein 2 , Non-alcoholic Fatty Liver Disease/blood , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/urine , Pilot Projects , Protein TransportABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is quickly becoming one of the most prominent causes of liver disease worldwide. The increasing incidence of NAFLD is tied to the obesity epidemic and the subsequent metabolic derangements brought along with it. Current efforts to elucidate the mechanism and causes of the disease have answered some questions, but much remains unknown about NAFLD. The aim of this article is to discuss the current knowledge regarding the pathogenesis of the disease, as well as the current and future diagnostic, preventative, and therapeutic options available to clinicians for the management of NAFLD.
Subject(s)
Epidemics , Non-alcoholic Fatty Liver Disease/epidemiology , Animals , Disease Progression , Humans , Incidence , Liver/metabolism , Liver/pathology , Metabolic Diseases/epidemiology , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/therapy , Obesity/epidemiology , Prognosis , Risk Factors , Time FactorsABSTRACT
The 11th Annual International Congress of Pediatric Hepatology, Gastroenterology and Nutrition, hosted by the Egyptian Pediatric Association in collaboration with the International Association for the Study of The Liver, provided a comprehensive review of different subjects related to pediatric hepatology, gastroenterology and nutrition. The meeting was chaired by Professor Mortada El-Shabrawi from Cairo University Children's Hospital and Professor Talal Abdel Aziz Farrag from the Military Medical Academy, Cairo, Egypt.
