Steatosis Alters the Activity of Hepatocyte Membrane Transporters in Obese Rats

Fat accumulation (steatosis) in ballooned hepatocytes alters the expression of membrane transporters in Zucker fatty (fa/fa) rats. The aim of the study was to quantify the functions of these transporters and their impact on hepatocyte concentrations using a clinical hepatobiliary contrast agent (Gadobenate dimeglumine, BOPTA) for liver imaging. In isolated and perfused rat livers, we quantified BOPTA accumulation and decay profiles in fa/+ (normal) and fa/fa hepatocytes by placing a gamma counter over livers. Profiles of BOPTA accumulation and decay in hepatocytes were analysed with nonlinear regressions to characterise BOPTA influx and efflux across hepatocyte transporters. At the end of the accumulation period, BOPTA hepatocyte concentrations and influx clearances were not significantly different in fa/+ and fa/fa livers. In contrast, bile clearance was significantly lower in fatty hepatocytes while efflux clearance back to sinusoids compensated the low efflux into canaliculi. The time when BOPTA cellular efflux impacts the accumulation profile of hepatocyte concentrations was slightly delayed (2 min) by steatosis, anticipating a delayed emptying of hepatocytes. The experimental model is useful for quantifying the functions of hepatocyte transporters in liver diseases.

Concentrations and pharmacokinetic parameters of MRI and SPECT hepatobiliary agents in rat liver compartments

Background In hepatobiliary imaging, systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes. They add in situ concentration of each compartment corrected by its respective volume ratio to provide liver concentrations. In vivo contribution of each compartment to liver concentration is inaccessible. Our aim was to quantify the compartmental distribution of two hepatobiliary agents in an ex vivo model and determine how their liver extraction ratios and cholestasis (livers lacking canalicular transporters) might modify it. Methods We perfused labelled gadobenate dimeglumine (Bopta, 200 μM, 7% liver extraction ratio) and mebrofenin (Meb, 64 μM, 94% liver extraction ratio) in normal (n = 18) and cholestatic (n = 6) rat livers. We quantified liver concentrations with a gamma counter placed over livers. Concentrations in hepatocytes and bile canaliculi were calculated. Mann-Whitney and Kruskal-Wallis tests were used. Results Hepatocyte concentrations were 2,043 ± 333 μM (Meb) versus 360 ± 69 μM (Bopta, p < 0.001). Meb extracellular concentrations did not contribute to liver concentrations (1.3 ± 0.3%). The contribution of Bopta extracellular concentration was 12.4 ± 1.9% (p < 0.001 versus Meb). Contribution of canaliculi was similar for both agents (16%). Cholestatic livers had no Bopta in canaliculi but their hepatocyte concentrations increased in comparison to normal livers. Conclusion Hepatocyte concentrations are correlated to liver extraction ratios of hepatobiliary agents. When Bopta is not present in canaliculi of cholestatic livers, hepatocyte concentrations increase in comparison to normal livers. This new understanding extends the interpretation of clinical liver images.

Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging

Membrane proteins responsible for transporting magnetic resonance (MR) and fluorescent contrast agents are of particular importance because they are potential reporter proteins in noninvasive molecular imaging. Gadobenate dimeglumine (Gd-BOPTA), a liver-specific MR contrast agent, has been used globally for more than 10 years. However, the corresponding molecular transportation mechanism has not been validated. We previously reported that the organic anion transporting polypeptide (OATP) 1B3 has an uptake capability for both MR agents (Gd-EOB-DTPA) and indocyanine green (ICG), a clinically available near-infrared (NIR) fluorescent dye. This study further evaluated OATP1B1, another polypeptide of the OATP family, to determine its reporter capability. In the OATP1B1 transfected 293T transient expression model, both Gd-BOPTA and Gd-EOB-DTPA uptake were confirmed through 1.5 T MR imaging. In the constant OAPT1B1 and OATP1B3 expression model in the HT-1080 cell line, both HT-1080-OAPT1B1 and HT-1080-OATP1B3 were observed to ingest Gd-BOPTA and Gd-EOB-DTPA. Lastly, we validated the ICG uptake capability of both OATP1B1 and OATP1B3. OAPT1B3 exhibited a superior ICG uptake capability to that of OAPT1B1. We conclude that OATP1B1 is a potential reporter for dual MR and NIR fluorescent molecular imaging, especially in conjunction with Gd-BOPTA.

Physicians with self-diagnosed gadolinium deposition disease: a case series

Objective: The objective of this study was to allow physicians with self-diagnosed gadolinium deposition disease symptoms to report their own experience. Materials and Methods: Nine physicians (seven females), with a mean age of 50.5 ± 8.3 years, participated in this case series. Nationalities were American (n = 6), British, Portuguese, and Romanian. Medical practices included internal medicine (n = 2), trauma surgery, ophthalmology, gastroenterology, psychiatry, family medicine, obstetrics/gynecology, and general practice. Results: Genetically, eight of the physicians were of central European origin. Underlying autoimmune conditions were present in four. Symptoms developed after a single injection in one physician and after multiple injections in eight. The precipitating agent was gadobenate dimeglumine in four physicians, gadobutrol in three, gadoterate meglumine in one, and gadopentetate dimeglumine in one. The most consistent symptoms were a burning sensation, brain fog, fatigue, distal paresthesia, fasciculations, headache, and insomnia. Eight of the physicians were compelled to change their practice of medicine. Conclusion: In the various physicians, gadolinium deposition disease showed common features and had a substantial impact on daily activity. Physicians are educated reporters on disease, so their personal descriptions should spark interest in further research.

Diagnostic evaluation and ablation treatments assessment in hepatocellular carcinoma

This article provides an overview of diagnostic evaluation and ablation treatment assessment in Hepatocellular Carcinoma (HCC). Only studies, in the English language from January 2010 to January 202, evaluating the diagnostic tools and assessment of ablative therapies in HCC patients were included. We found 173 clinical studies that satisfied the inclusion criteria.HCC may be noninvasively diagnosed by imaging findings. Multiphase contrast-enhanced imaging is necessary to assess HCC. Intravenous extracellular contrast agents are used for CT, while the agents used for MRI may be extracellular or hepatobiliary. Both gadoxetate disodium and gadobenate dimeglumine may be used in hepatobiliary phase imaging. For treatment-naive patients undergoing CT, unenhanced imaging is optional; however, it is required in the post treatment setting for CT and all MRI studies. Late arterial phase is strongly preferred over early arterial phase. The choice of modality (CT, US/CEUS or MRI) and MRI contrast agent (extracelllar or hepatobiliary) depends on patient, institutional, and regional factors. MRI allows to link morfological and functional data in the HCC evaluation. Also, Radiomics is an emerging field in the assessment of HCC patients.Postablation imaging is necessary to assess the treatment results, to monitor evolution of the ablated tissue over time, and to evaluate for complications. Post- thermal treatments, imaging should be performed at regularly scheduled intervals to assess treatment response and to evaluate for new lesions and potential complications.