Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green
Authors: Sabine Schmidt, Alban Denys, Catherine M. Pastor
Journal: Journal of Hepatology (2013)

Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine greenJournal of HepatologyVol. 58Issue 2PreviewAlthough recent advances in preoperative imaging have enabled accurate estimation of the regional liver volume with venous occlusion, the extent of functional decrease in such regions remains unclear. In this study, the portal uptake function in postoperative veno-occlusive regions and non-veno-occlusive regions was evaluated by intraoperative fluorescent imaging after intravenous injection of indocyanine green (ICG). Full-Text PDF Reply to: "Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green"Journal of HepatologyVol. 59Issue 3PreviewWe have read with interest the comments made by Kobbe et al. to our recently published article, which demonstrated that portal uptake of indocyanine green (ICG) in veno-occlusive regions caused by dissection of the major hepatic veins decreased to approximately 40% of that in non-veno-occlusive regions (ranging from 10% to 80%) by using intraoperative fluorescence imaging [1]. In veno-occlusive hepatic regions, the portal veins can act as drainage of arterial blood flow, according to the severity of venous occlusion. Full-Text PDF Open Access We have read with great interest the article by Kawaguchi et al. [[1]Kawaguchi Y. Ishizawa T. Miyata Y. Yamashita S. Masuda K. Satou S. et al.Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green.J Hepatol. 2013; 58: 247-253Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. The authors measured, in the operating room, the hepatic concentrations of indocyanine green (ICG) to evaluate the function of congestive hepatic segments. Three groups of patients were studied: partial hepatectomy, remnant liver of living donors, and hepatic grafts of recipients. Although preoperative three-dimensional computer tomography estimates the postoperative segment volumes, the function of congestive segments is not evaluated by the imaging technique. Interestingly, the authors showed that, following ICG injection, the dye concentrations were significantly lower in congestive than non-congestive segments. ICG hepatic uptake rates were also decreased in the congestive segments of the three groups of patients. However, the concentrations of ICG and ICG hepatic uptake rates greatly varied (between 10 and 80% of the values in non-congestive segments). Thus, some congestive segments conserve a near normal function while others have a poor hepatic ICG uptake rate. Even though peroperative ultrasonography detects anastomoses between hepatic veins, favouring blood drainage from congestive areas, the hepatic function of most congestive regions remain unknown. The congestive segments with poor function decrease the overall postoperative recovery, induce complications, and slow hepatic regeneration. These segments can be treated by hepatic venous reconstruction to better drain outflow. Interestingly, congestive segments V have higher ICG uptake than segments VIII and these latter segments benefit from hepatic vein reconstruction more than segments V do. Thus, the use of a camera with fluorescence imaging in the operating room can estimate the function of congestive segments and modify the surgical procedures. The reason why ICG concentrations were lower in congestive segments was puzzling and the authors suggested that ICG flowing into sinusoids regurgitates back to portal veins without entering the extracellular space and without reaching hepatocytes. The transport of ICG through hepatocytes might also be involved. ICG enters human hepatocytes through the Organic Anion Transporting Polypeptides B3 (OATP1B3) and Na(+)/Taurocholate Cotransporting Polypeptide (NTCP) [[2]de Graaf W. Häusler S. Heger M. van Ginhoven T.M. van Cappellen G. Bennink R.J. et al.Transporters involved in the hepatic uptake of (99m)Tc-mebrofenin and indocyanine green.J Hepatol. 2011; 54: 738-745Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar]. The dye is likely to exit without transformation through the multiple resistance-associated protein 2 (MRP2). The expression of human transporters was never investigated in the congestive human hepatic segments described in the study. However, a decreased hepatic uptake through OATP1B1/B3 transporters has already been published in another chronic congestive pathology of the liver, the sinusoidal obstruction syndrome. Thus, sinusoidal obstruction syndrome following chemotherapy is associated with blood stasis inside sinusoids and patients with this syndrome have heterogenous hypointensities (decreased uptake) at magnetic resonance imaging (MRI) after injection of the hepatobiliary contrast agent Gd-EOB-DTPA [[3]Shin N.Y. Kim M.J. Lim J.S. Park M.S. Chung Y.E. Choi J.Y. et al.Accuracy of gadoxetic acid-enhanced magnetic resonance imaging for the diagnosis of sinusoidal obstruction syndrome in patients with chemotherapy-treated colorectal liver metastases.Eur Radiol. 2012; 22: 864-871Crossref PubMed Scopus (84) Google Scholar]. In rats treated with monocrotaline (a toxic that induces sinusoidal obtruction syndrome), the hepatic concentrations and bile excretion of Gd-BOPTA are also lower than in control rats (Fig. 1) [[4]Schiffer E. Frossard J.L. Rubbia-Brandt L. Mentha G. Pastor C.M. Hepatic regeneration is decreased in a rat model of sinusoidal obstruction syndrome.J Surg Oncol. 2009; 99: 439-446Crossref PubMed Scopus (38) Google Scholar]. Gd-BOPTA is another hepatobiliary contrast agent close to Gd-EOB-DTPA that enters rat hepatocytes through rat Oatps and is excreted into bile through the canalicular transporter rat Mrp2 [5Millet P. Moulin M. Stieger B. Daali Y. Pastor C.M. How organic anions accumulate in hepatocytes lacking Mrp2: evidence in rat liver.J Pharmacol Exp Ther. 2011; 336: 624-632Crossref PubMed Scopus (25) Google Scholar, 6Planchamp C. Hadengue A. Stieger B. Bourquin J. Vonlaufen A. Frossard J.-L. et al.Function of both sinusoidal and canalicular transporters controls the concentration of organic anions within hepatocytes.Mol Pharmacol. 2007; 71: 1089-1097Crossref PubMed Scopus (41) Google Scholar]. Interestingly, rats with sinusoidal obstruction syndrome have decreased regeneration rates following partial hepatectomy (70%). The study by Kawaguchi et al. [[1]Kawaguchi Y. Ishizawa T. Miyata Y. Yamashita S. Masuda K. Satou S. et al.Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green.J Hepatol. 2013; 58: 247-253Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar] reinforces the growing interest in hepatobiliary compounds that use the OATPs/MRP2 pathway through hepatocytes to evaluate the hepatic function of patients. Dyes (ICG), MR contrast agents (Gd-BOPTA and Gd-EOB-DTPA), and tracers (99mTc-mebrofenin) have been evaluated and the results of these studies are summarized in several recent reviews [7Hoekstra L.T. de Graaf W. Nibourg G.A. Heger M. Bennink R.J. Stieger B. et al.Physiological and biochemical basis of clinical liver function tests: a review.Ann Surg. 2013; 257: 27-36Crossref PubMed Scopus (238) Google Scholar, 8Stieger B. Heger M. de Graaf W. Paumgartner G. van Gulik T. The emerging role of transport systems in liver function tests.Eur J Pharmacol. 2012; 675: 1-5Crossref PubMed Scopus (34) Google Scholar, 9Van Beers B.E. Pastor C.M. Hussain H.K. Primovist, eovist: what to expect?.J Hepatol. 2012; 57: 421-429Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar]. These articles describe how clearance tests and liver imaging with hepatobiliary compounds improve the scoring of hepatic function. Moreover, imaging the entire liver with dyes, contrast agents, or tracers offers an advantage over plasma biomakers since it studies all segments of the liver [[10]Yamada A. Hara T. Li F. Fujinaga Y. Ueda K. Kadoya M. et al.Quantitative evaluation of liver function with use of gadoxetate disodium-enhanced MR imaging.Radiology. 2011; 260: 727-733Crossref PubMed Scopus (157) Google Scholar]. However, as pointed out by the authors, transport through this pathway does not represent all functions of hepatocytes. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.