GastrointestinalAlterations in hepatic lobar function in regenerating rat liver
Introduction
Curative liver resection provides the best survival rate for patients with liver malignancies [1]. Extended hepatectomy is usually required to achieve negative margins. Excessive removal of the hepatic parenchyma, however, often leads to postoperative liver failure. The most widely used method to overcome this problem is preoperative enlargement of the future liver remnant (FLR) volume by portal vein occlusion (PVO) techniques, such as portal vein embolization, two-stage hepatectomy combined with portal vein ligation, and more recently associating liver partition with portal vein ligation for staged hepatectomy. These surgical procedures are applied to redirect portal blood flow away from the liver lobes designated for resection, toward the anticipated FLR resulting in FLR hypertrophy (regeneration) [2].
Currently, computed tomography (CT) volumetry is the standard method for determining whether sufficient regeneration is present after PVO. Nevertheless, increase in the FLR volume (morphologic regeneration) does not necessarily reflect the actual alterations of the FLR function (functional regeneration) [3]. Although the morphologic phenomena have been widely discussed, little is known about the functional alterations occurring after PVO because of the lack of an ideal quantitative test, which would represent multiple aspects of the liver function and would be able to assess FLR function selectively. There are two contradictory theories in the literature. Some studies postulate that liver regeneration is promoted at the expense of liver function, resulting in prolonged and less functional regeneration compared with the rapid increase in FLR volume [4], [5], [6]. Other works, based on nuclear imaging techniques (i.e., hepatobiliary scintigraphy [7] or hepatocyte mass scintigraphy [8], [9]), indicate that increase in FLR function is more pronounced than implied by the degree of morphologic regeneration. This hypothesis, however, has not yet been confirmed by other widely accepted quantitative liver function tests.
Over the last decades, several quantitative liver function tests have been developed, of which the indocyanine green (ICG) clearance test is the most common. ICG is a fluorescent tricarbocyanine dye exclusively eliminated by the liver without metabolism and enterohepatic recirculation [10]. Although ICG is not metabolized, it follows a path of intracellular transport similar to several exogenous and endogenous molecules; its disappearance from the blood, therefore, provides indirect information about the overall function of the liver. The main limitation of the test is that it does not take into account regional variations in liver quality that may occur after PVO.
Selective biliary drainage, however, enables us to assess biliary ICG excretion selectively in FLR. Literary data have demonstrated that biliary ICG excretion is an excellent indicator of liver function or dysfunction in various pathologic conditions such as liver ischemia–reperfusion, liver transplantation, or severe septic state [11], [12], [13]. Furthermore, the capacity of the liver to excrete ICG accurately reflects the intracellular adenosine triphosphate (ATP) level and hence the energy status of hepatocytes, which are among the most decisive factors in terms of functionality and organ viability [14].
The aim of the present study was to selectively assess the time-dependent reactions of regional hepatic function to portal vein ligation by selective biliary drainage and assessment of biliary ICG excretion compared with the conventional parameters of liver regeneration and hepatic circulation.
Section snippets
Materials and methods
The experimental design was regulated in accordance with the National Institutes of Health guidelines for animal care and was approved by the Committee on Animal Experimentation of Semmelweis University (license number: PEI/001/313-4/2014). Male Wistar rats weighing 200–250 g were used (Semmelweis University, Central Animal Facility, Budapest, Hungary). Standard rat chow and water were provided ad libitum. Before the experiment, the rats were fasted overnight to minimize the effect of food
Hemodynamics and liver microcirculation
Mean arterial pressure remained around the baseline level during the experiments (Fig. 2A). Portal pressure increased significantly 1 d after the operation (P < 0.001; day 1 versus day 0) and remained elevated until the seventh day (P = 0.02; day 7 versus day 0; Fig. 2B).
Microcirculatory blood flow of the PVNL lobes increased immediately after portal vein ligation and remained elevated until the third day (P < 0.001; day 3 versus day 0). On the fifth day, it returned to the values detected
Discussion
In the present study, the effects of portal vein ligation on the functional capacity of the hepatic lobes were studied in addition to the liver circulation and conventional parameters of liver regeneration (morphologic regeneration).
In our 80% portal vein ligation model, although the systemic circulation was not affected, considerable alterations were seen in liver hemodynamics. Immediately after the operation, the portal pressure and microcirculatory blood flow of PVNL lobes showed substantial
Conclusions
In summary, portal vein ligation resulted in temporary impairment of total liver excretory function (indicated by ICG clearance test and biliary ICG excretion), caused by the functional deterioration of both PVL and PVNL lobes. This observation indicates that liver regeneration is initially promoted at the expense of the liver function. After the peak of cell division, however, an overcompensatory response was manifest in the PVNL lobes, during which the lobar liver function underwent more
Acknowledgment
The authors thank Dr László Tretter and Dr Kraszimir Kolev (Department of Medical Biochemistry, Semmelweis University, Hungary) for their assistance in spectrophotometric measurements.
Authors' contributions: A.F., L.H., and A.S. conceived and designed the experiments. A.F., A.B., K.D., and S.P. performed the experiments. A.F., G.L., and Z.C. analyzed the data. G.L., K.D., and S.P. contributed reagents, materials, and analysis tools. A.F., Z.C., and A.S. wrote the article.
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