Gastrointestinal
Alterations in hepatic lobar function in regenerating rat liver

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Abstract

Background

Ligation of a branch of the portal vein redirects portal blood to nonligated lobes resulting in lobar hypertrophy. Although the effect of portal vein ligation on liver volume is well documented, the parallel alterations in liver function are still the subject of controversy. Our aim was to assess the time-dependent reactions of regional hepatic function to portal vein ligation by selective biliary drainage.

Methods

Male Wistar rats (n = 44) underwent 80% portal vein ligation. Before the operation as well as 1, 2, 3, 5, and 7 d after circulation, morphology and function (laboratory blood test; hepatic bile flow; plasma disappearance rate of indocyanine green; and biliary indocyanine green excretion) of the liver were examined.

Results

Although portal vein ligation affected liver circulation and morphology to a great extent, serum albumin levels, bilirubin levels, and total hepatic bile flow did not change significantly after the operation. Nevertheless, plasma disappearance rate and biliary indocyanine green excretion indicated a temporary impairment of total liver function with the lowest value on the second day and normalization by the fifth day. Bile production and biliary indocyanine green excretion of ligated lobes decreased rapidly after the operation and remained persistently suppressed, whereas the secretory function of nonligated lobes—after a temporary decline—showed a greater increase than the weight of the lobes.

Conclusions

Portal vein ligation induced temporary impairment of total liver function, followed by rapid recovery mainly by reason of increase in the function of nonligated lobes. Functional increase in nonligated lobes was more pronounced than suggested by the degree of volume gain.

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.

References (33)

  • K.P. van Lienden et al.

    Portal vein embolization before liver resection: a systematic review

    Cardiovasc Interv Radiol

    (2013)
  • K. Izuishi et al.

    Microsomal cytochrome P-450 monooxygenase system and its drug-metabolizing activity after partial portal vein ligation in the rat

    World J Surg

    (1999)
  • W. de Graaf et al.

    Increase in future remnant liver function after preoperative portal vein embolization

    Br J Surg

    (2011)
  • Y. Yumoto et al.

    Preoperative estimation of remnant hepatic function using fusion images obtained by (99m)Tc-labelled galactosyl-human serum albumin liver scintigraphy and computed tomography

    Br J Surg

    (2010)
  • T. Beppu et al.

    Liver functional volumetry for portal vein embolization using a newly developed 99mTc-galactosyl human serum albumin scintigraphy SPECT-computed tomography fusion system

    J Gastroenterol

    (2011)
  • A. Szijarto et al.

    Two-staged procedure of portal ligation and hepatectomy monitored by ICG clearance

    J Invest Surg

    (2009)
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