C Zapletal

Assessment of hepatic perfusion in pigs by pharmacokinetic analysis of dynamic MR images

The purpose of this study was to evaluate a new method based on magnetic resonance imaging for the characterization of hepatic perfusion. In nine pigs dynamic MRI was performed before and after partial occlusion of the portal vein. The pharmacokinetic analysis of the contrast enhancement resulted in a set of parameters (amplitude, A; perfusion rate, kp; elimination rate, kel; lag time, tlag) of which kp was expected to correlate with hepatic perfusion. Reference measurements were done with ultrasound flowmeters and with a thermal diffusion probe (TDP). MR perfusion rate kp significantly dropped under partial portal vein occlusion from an average of 11.3 to 4.9 min−1 (P < 0.001), while the difference in amplitude A was not significant. The correlation between kp and the TDP measurement was r = 0.89 (P < 0.001). Pharmacokinetic analysis of MRI contrast enhancement provides a non‐invasive assessment of hepatic perfusion.J. Magn. Reson. Imaging 1999;9:568–572.

Ischemic preconditioning improves liver microcirculation after ischemia/reperfusion.

THE ISCHEMIA/REPERFUSION injury plays an important role in liver transplantation and surgery. Oxidative stress after reperfusion results in activation and adherence of leucocytes and platelets. Consequently, alterations in microcirculation develop that lead to impairment of hepatic function. In 22% of the cases extensive reperfusion injury causes severe deterioration of microcirculation leading to primary dysfunction or primary graft failure. A more detailed understanding of pathophysiological mechanisms resulting into treatment possibilities is therefore essential. Ideal treatment makes use of intrinsic protective mechanisms and is offered before damage takes place. Ischemic preconditioning takes that into account. Ischemic preconditioning describes the phenomenon that a brief ischemia and reperfusion, the so-called preclamping, increases the ischemic tolerance of a following ischemic period. It was first described for the heart in 1986 by Murry and since then has been extensively examined. Studies concerning other organs such as muscle and kidney followed. The first study about preclamping in the liver was performed in 1993 by Lloris-Carsi et al. He and others studied different preclamping and reperfusion times, focusing on laboratory liver function tests, energy content of the tissue, histological analyses of cellular integrity, and survival after sublethal stress. The underlying effect of ischemic preconditioning has been of special interest ever since. Some substances such as heat shock protein, adenosine, and nitric oxide (NO) seem to be involved, the exact mechanism has not yet been identified. Thus far, analyses of liver microcirculation after ischemic preconditioning have not been performed. Microcirculatory disturbances can directly be related to organ function and, therefore, to the extent of ischemia/reperfusion injury, respectively, to the benefit of an applied treatment. Therefore, it was the goal of this study to evaluate the effect of ischemic preconditioning on the hepatic microcirculation after warm ischemia/reperfusion by intravital microscopy in rats.

Sequential (domino) transplantation of the liver in a transthyretin-50 familial amyloid polyneuropathy

Abstract Background: General shortage of cadaveric organs has led to a search for alternative methods to expand the donor pool. Sequential (domino) transplantation is yet another attempt to compensate for the declining consent to organ donation. Patients and methods: To qualify for a domino liver transplantation, the following preconditions must be fulfilled: (1) extrahepatic disease must exist, (2) liver must be fully functional, and (3) the genetic defect in the host should recur within a sufficient latency period. Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease which involves a genetic defect for transthyretin (TTR), which is predominantly produced in the liver. Results: In this report, we describe a rare case of a FAP TTR-50 variant undergoing domino liver transplantation. Since myocardial symptoms precede peripheral polyneuropathy, special emphasis should be placed on arrhythmias and the restrictive cardiomyopathy necessitating a veno-venous bypass or a cardiac pacemaker in order to improve cardiac contractility. The type of anastomosis of the suprahepatic inferior vena cava and possible alternatives are discussed. Conclusion: Despite ethical problems, the advantages of the domino procedure are obvious: (1) expansion of the donor pool, (2) ability to use living donors, and (3) presence of very short ischemic time and thus excellent liver function. Due to the kinetics of TTR production and deposition, donors and recipients of FAP livers should be followed up using an extensive neurological and cardiological protocol.

The influence of selenium substitution on microcirculation and glutathione metabolism after warm liver ischemia/reperfusion in a rat model.

Ischemia/reperfusion (I/R) injury is a variable yet unavoidable complication in liver surgery and transplantation. Selenium-dependent glutathione-peroxidases (GPx) and selenoproteins function as antioxidant defense systems. One target in preventing I/R injury is enhancing the capacity of endogenous redox defense. It was the aim of this study to analyze the effects of selenium substitution on liver microcirculation, hepatocellular injury and glutathione status in a model of partial warm liver ischemia in the rat. Sodium selenite was administered in three different dosages i.v.: 0.125 microg/g, 0.25 microg/g and 0.375 microg/g body weight and compared to an untreated control group (each n=10). Intravital microscopy was performed after 70 min of partial warm liver ischemia and 90 min of reperfusion. Liver tissue and plasma samples were taken at the end of the experiment for laboratory analysis. Microcirculation improved significantly in all therapy groups in contrast to control animals. ALT levels decreased significantly whereas malondialdehyde levels remained unchanged. In liver tissue, selenium supplementation caused an increase in the amount of total and reduced glutathione without changes in oxidized glutathione. This effect is likely mediated by selenite itself and selenoprotein P rather than by modulating GPx activity. We were able to show that selenite substitution has an immediate protective effect on I/R injury after warm hepatic ischemia by acting as a radical scavenger and preserving the antioxidative capacity of the liver.

Quantification of liver perfusion by dynamic magnetic resonance imaging: Experimental evaluation and clinical pilot study

Changes in liver microcirculation are considered essential in assessing ischemia‐reperfusion injury, which in turn has an impact on liver graft function and outcome following liver transplantation (LTx). The aim of this study was to introduce dynamic magnetic resonance imaging (dMRI) as a new technique for overall quantification of hepatic microcirculation and compare it to perfusion measured by laser Doppler flowmetry (LDF; hepatic artery/portal vein) and thermal diffusion (TD). The study included 3 groups, measuring hepatic blood flow and microcirculation with the help of TD, LDF, and dMRI. In group I (9 landrace pigs; 26 ± 5 kg), the native liver before and after partial portal occlusion was studied; in group II (6 landrace pigs; 25.5 ± 4.4 kg), the liver 24 hours after LTx was studied; and in group III (14 patients), the liver on days 4 to 7 following LTx was studied. A close correlation was found between dMRI measurements and TD (r = 0.7–0.9, P < 0.01) in 4 defined regions of interest. Portal blood flow and partial occlusion of the portal vein were accurately detected by LDF flowmetry and correlated well with dMRI (r = 0.95, P < 0.01). In the clinical setting, representative TD measurements in segment 4b of the transplanted liver correlated well with dMRI analysis in other segments. Quantification of the portal blood flow and imaging of the whole liver could be performed simultaneously by dMRI. In conclusion, dMRI has been proved to be a sensitive modality for the quantification of liver microcirculation and hepatic blood flow in experimental and clinical LTx. It allows for a synchronous, noninvasive assessment of macrocirculation and microcirculation of the liver and could become a valuable diagnostic tool in advanced liver surgery and transplantation. Liver Transpl 15:693–700, 2009.

Impairment of hepatic microcirculation as an early manifestation of acute rejection after clinical liver transplantation

DURING REJECTION episodes after liver transplantation, T cell activation is partly the result of intracellular adhesion molecule–I (ICAM-I) expression on hepatocytes. As an adhesion molecule, ICAM-I generally induces leucocyte-endothelium interaction in the liver predominantly along postsinusoidal venules. An increase of endothelial leucocyte adherence is considered to be a mechanism of hepatic microcirculatory impairment after ischemia and reperfusion. However, clinical data on potential changes of hepatic microcirculation during rejection are missing. After experimental validation, thermodiffusion represents a tool to allow continuous monitoring of liver microcirculation during the first week postoperatively. It was the goal of this study to quantify hepatic microperfusion in patients with early rejection.

STORUNG DER HEPATISCHEN MIKROZIRKULATION ALS FRUHMANIFESTATION DER REJEKTION BEI KLINISCHER LEBERTRANSPLANTATION

Im Rahmen einer Rejektion nach Lebertransplantation erfolgt die T-Zellaktivierung u. a. durch ICAM-1 Expression auf Hepatozyten [1]. Als Adhasionsmolekul vermittelt ICAM-1 ubiquitar die Leukozyten-Endothel Interaktion, in der Leber insbesondere im Bereich der postsinusoidalen Venolen [2]. Eine Zunahme der endothelialen Leukozytenadharenz wird als ein Hauptmechanismus der hepatische Mikrozirkulationsstorung nach Ischamie und Reperfusion angesehen. Allerdings fehlen klinische Untersuchungen zu moglichen Anderungen der hepatischen Mikrozirkulation bei Rejektion. Nach experimenteller Validierung steht mit der Technik der Thermodiffusion erstmalig ein Verfahren zur Verfugung, das ein kontinuierliches Monitoring der Lebermikrozirkulation wahrend einer Woche postoperativ erlaubt [3, 4]. Ziel der vorliegenden Studie war die Quantifizierung der hepatischen Mikroperfusion bei Patienten mit fruher Rejektion.