Gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging as a useful detection method for advanced primary biliary cirrhosis
Abstract:Aim:In primary biliary cirrhosis (PBC), damaged hepatocytes resulting from chronic cholestasis follow a compensatory mechanism that alters hepatobiliary transporter expression to reduce the accumulation of potentially toxic compounds such as bile acid. Organic anion transporter peptide 1B3 (OATP1B3), which transports agents such as gadolinium-ethoxybenzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA), has reduced expression in the late stages of PBC. Therefore, we investigated the use of Gd-EOB-DTPA-enhance… Show more
“…Several studies have reported that the mRNA and protein expression of NTCP, OATP1B1, and OATP1B3 are downregulated in PBC as compared to normal liver. 189–192 These findings suggest the potential adaptation by hepatocytes to limit the accumulation of toxic bile acids. 189 …”
Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. While extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and/or function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and of efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma (HCC), human immunodeficiency virus (HIV) infection, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and primary biliary cirrhosis (PBC) are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition.
“…Several studies have reported that the mRNA and protein expression of NTCP, OATP1B1, and OATP1B3 are downregulated in PBC as compared to normal liver. 189–192 These findings suggest the potential adaptation by hepatocytes to limit the accumulation of toxic bile acids. 189 …”
Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. While extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and/or function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and of efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma (HCC), human immunodeficiency virus (HIV) infection, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and primary biliary cirrhosis (PBC) are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition.
“…It has been shown that the pharmacokinetics of drugs which are substrates of hepatic transporters is altered in patients with hepatic insufficiency . There is, however, a lack of quantitative data on protein abundance of hepatic transporters in patients with compromised liver function, and most of the studies have been performed using nonprecise methods, such as immunoblotting .…”
Hepatocellular transporter levels were quantified using quantitative reverse transcription polymerase chain reaction and liquid chromatography-tandem mass spectrometry methods. Liver function deterioration (Child-Pugh class C) produced significant protein abundance (mean values) increase (to healthy livers) in P-gp (to 260% (CV (coefficient of variation) 82%)) and MRP4 (CV 230%) (not detected in healthy livers), decrease in MRP2 (to 30% (CV 126%)), NTCP (to 34% (CV 112%)), OCT1 (to 35% (CV 153%)), OATP1B1 (to 46% (CV 73%)), and OATP2B1 (to 27% (CV 230%)), whereas BSEP (CV 99%), MRP3 (CV 106%), OAT2 (CV 97%), OCT3 (CV 113%), and OATP1B3 (CV 144%) remained unchanged. Alcoholic liver disease produced significant protein downregulation of MRP2 (to 30% (CV 134%)), NTCP (to 76% (CV 78%)), OAT2 (to 26% (CV 117%)), OATP1B1 (to 61% (CV 76%)), OATP1B3 (to 79% (CV 160%)), and OATP2B1 (to 73% (CV 90%)) of healthy tissue values. Hepatitis C produced BSEP (to 47% (CV 99%)) and OATP2B1 (to 74% (CV 91%)) protein reduction. Primary biliary cholangitis and primary sclerosing cholangitis demonstrated P-gp and MRP4 protein upregulation (to 350% (CV 47%) and 287% (CV 38%), respectively). Autoimmune hepatitis revealed P-gp (to 410% (CV 49%)) and MRP4 (CV 96%) increase, and MRP2 (to 18% (CV 259%)) protein decrease. Drug transporters' protein abundance depends on liver pathology type and its functional state.Drug transporters have a major impact on the overall drug disposition, efficacy, toxicity, and drug-drug interactions. While transporters present at the basolateral membrane mediate the uptake of substrates from blood into hepatocytes and/or efflux of substrates in the opposite direction, transporters at the canalicular membrane mediate the excretion of substrates into bile. Transporters present in intracellular membranes sequester substrates in subcellular compartments within hepatocytes. The expression and function of transporters are subjected to complex regulatory mechanisms and may be affected by liver disease states and liver dysfunction.
“…The portal halo sign is the most typical feature of PBC, although it may sometimes also be found in autoimmune hepatitis-PBC overlap [ 51 ]. This sign is observed only in patients with later stages of the disease (fibrosis stage II or greater), and the prevalence tends to increase with the increase in the fibrosis stage [ 37 , 38 , 52 ]. Fig.…”
Primary biliary cholangitis (PBC) is a rare chronic autoimmune-mediated cholestatic liver disease involving medium and small bile ducts that can lead to liver fibrosis and cirrhosis. To date, the pathogenesis of PBC remains elusive, and there is currently no curative medical treatment. Computed tomography (CT) and magnetic resonance (MR) imaging, as common technical tools that allow non-invasive monitoring of liver tissue in vivo, play crucial roles in the diagnosis, staging, and prognosis prediction in PBC by enabling assessment of abnormalities in liver morphology and parenchyma, irregular configuration of bile ducts, lymphadenopathy, portal hypertension, and complications of cirrhosis. Moreover, CT and MRI can be used to monitor the disease progression after treatment of PBC (e.g. the onset of cirrhotic decompensation or HCC) to guide the clinical decisions for liver transplantation. With the optimization of imaging technology, magnetic resonance elastography (MRE) offers additional information on liver stiffness, allows for the identification of early cirrhosis in PBC and provides a basis for predicting prognosis. Gadoxetic acid-enhanced MRI enables the assessment of liver function in patients with PBC. The purpose of this review is to detail and illustrate the definition, pathological basis, and clinical importance of CT and MRI features of PBC to help radiologists and clinicians enhance their understanding of PBC.Critical Relevance StatementCharacteristic CT and MR imaging manifestations of primary biliary cholangitis may reflect the course of the disease and provide information associated with histological grading and altered cellular function.Key points• Imaging has become highly useful for differentiating PBC from other diseases.• Key pathological alterations of PBC can be captured by CT and MRI.• Characteristic manifestations provide information associated with histological grade and cellular function.• Despite this, the CT or MRI features of PBC are not specific.
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