UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Functional recovery after liver resection
Veteläinen, R.L.
Publication date
2006
Link to publication
Citation for published version (APA):
Veteläinen, R. L. (2006). Functional recovery after liver resection.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)
and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open
content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please
let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material
inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter
to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You
will be contacted as soon as possible.
Wilmarr de Graaf
Reetaa Vetelainen
Arlènee van Vliet
Roeloff J. Bennink
Thomass M. van Gulik
ii ; r i . « . . ' =~ rr r S-. -- a, '_
t t
..
v*
5
,!-' ' ^-".. r" s - . . %% a S - . . :rr Qii n Tt':Vi-~U U 1 ' T l l , 22 S, ff i , - _ i " , . , W** 'i ' I .. « $ " :ftt i^^0i^W^^0i^W
; ;
i i
r--' r--' r--' r--'r--' " r - , . r--' . r--' "
^.^^^^J^m^ÊÊBB^^-^,^ ^.^^^^J^m^ÊÊBB^^-^,^
Introduction n
Surgicall resection is the most effective treatment for patients with primary or secondary hepaticc malignancies. Owing to the improved surgical techniques and perioperative care, extendedd resections are now performed with greater frequency. Extended resections can resultt in a small postoperative remnant liver, thereby increasing the risk of postoperative liverr failure, especially in patients with chronic liver disease 1-2. Despite intensive care treatment,, the mortality of liver failure is substantial. Although the causes of liver failure are multifactorial,, the function of the postoperative remnant liver is main contributing factor. Therefore,, preoperative evaluation of the future remnant liver (FRL) function is important whenn deciding the operative limits of safe liver resection. The availability of preoperative portall vein embolization (PVE) has further increased the importance of preoperative assessmentt of hepatic function 3 7. PVE induces atrophy of the embotized, tumor bearing liverr segments while compensatory hypertrophy occurs of the non-embolized segments, herebyy increasing volume and function of the FRL 8. The individual response to VPE is variablee 9. Consequently, the quantification of hypertrophy of the non-embolized liver segmentss after PVE is a necessity.
Afterr partial liver resection, the liver has a unique ability to regenerate. This capacity is influencedd by multiple factors, including several underlying parenchymal liver diseases 10. Consequently,, it is important to evaluate the regeneration process after partial hepatectomy. Inn the last decades, several applications have been developed for the assessment of hepatic functionn including CT volumetry, numerous blood clearance tests and clinical classification systems.. Recently, technetium-99m (99mTc-) labeled -diethylenetriamine pentaacetic acid galactosyll human serum albumin (99mTc-GSA) scintigraphy and hepatobiliary scintigraphy (HBS)) with 99mTc- labeled iminodiacetic acid (IDA) have been developed as non-invasive alternativess for the evaluation of quantitative liver function. This review discusses in detail thee biochemical and technical background, as well as the clinical applications of 99mTc-GSA scintigraphyy and HBS with 99mTc- IDA analogues in the assessment of hepatic function in liverr surgery and transplantation.
Thee development of new techniques for assessment of liver function
Thee Conventional, preoperative selection of patients with cirrhosis is based on the clinical gradingg system of Child-Pugh (CP)]1. This system is based on five parameters, including the presencee or absence of encephalopathy and ascites, serum level of total bilirubin, serum levell of albumin and prothrombin time. The CP provides only indirect information about the FRLL function and can be unreliable for predicting the outcome of liver resections 12'13. Bloodd clearance tests, such as indocyanine green clearance (ICG), galactose elimination capacityy (GEC) and, caffeine clearance, have been employed as quantitative liver function tests.. In Eastern Asia, ICG clearance is frequently used to evaluate preoperative liver functionn 14. ICG is a tricarbocyanine dye, exclusively cleared from plasma by hepatocyte transporterss located on the baso-lateral membrane and excreted into the bile without intrahepaticc conjugation 15. The ICG clearance test can be expressed as the retention timee at 15 minutes (1CGR15), ICG clearance rate (ICGK), and ICG clearance at 15 minutes (ICGK15). .Galactosee elimination capacity (GEC) measures the rate of galactose elimination from the bloodd which depends mainly on phosphorylation of galactose by galactokinase within the hepatocytee cytoplasm 15. Both ICG clearance and GEC provide prognostic information in liverr diseases such as fulminant hepatic failure 17 and primary biliary cirrhosis 18. Some studiess have shown the ability of preoperative ICG 15 14'19 and GEC20 to predict morbidity andd mortality after partial hepatectomy. However, ICG clearance is dependent on hepatic bloodd flow and does not always correlate with postoperative outcome 12'21. Furthermore, alll blood clearance tests measure global liver function and do not provide information on thee distribution of function among the liver segments..
Monoethylglycinexylididee (MEGX) test has been introduced as a quantitative liver functionn test to measure hepatic cytochrome p450 activity u. The hepatic metabolism
off intravenously administered lidocaine, through the cytochrome p450 pathway, results inn the formation of MEGX. A correlation between decreased plasma MEGX values and increasedd risk of liver insufficiency after hepatic resection in patients with HCC has been demonstratedd 23<24. However, the MEGX test is affected by changes in the hepatic blood floww and by drugs that interfere the cytochrome p450 pathway 25. Furthermore, similar too other blood clearance tests, MEGX test only provides information on global liver function. .
Volumetricc assessment of the liver is frequently used as an indirect measurement of liver functionn 1'2'26'27. The FRL volume can be measured preoperatively by 3-D volumetric computerr tomography (CT) reconstruction. Preoperative volumetric assessment of the liver iss widely used as a guideline to exclude patients from liver resection or to select patients whoo will benefit from PVE (8). In patients with a non-compromised liver parenchyma, aa safe resection can be performed if the FRL volume is larger than 25-30% of total preoperativee liver volume 1'27. However, in patients with parenchymal liver disease, the safetyy limit is more variable and is around 40% of total liver volume 28. Parenchymal liverr diseases, such as cirrhosis, fibrosis and steatosis can affect total and segmental liver function.. Preoperative liver biopsy is currently the most reliable method to assess the liver parenchyma.. However, invasive liver biopsies bear a risk of severe complications, and are thereforee not routinely performed 29'30. Furthermore, multiple biopsies are required for a reliablee assessment of the liver parenchyma due to potentially unequal distribution of the liverr disease. Consequently, the histopathology of the liver parenchyma is often unknown beforee liver surgery. As a result, the assessments of FRL volume by CT volumetry can be unreliablee and unrepresentative for the actual liver function.
Duee to the limitations of conventional liver function tests, new applications are being developed.. A successful liver function test should be noninvasive, reliable, safe, inexpensive andd it should provide quantitative information on total and regional liver function. Moreover,, the test should be applicable both in patients with a normal liver as well as in patientss with a compromised liver.
Inn the last decades, functional imaging techniques with 99mTc-GSA liver scintigraphy and HBSS with different 99mTc-IDA analogues have been developed as simple, non-invasive methodss for evaluating total and regional quantitative liver function.
99m
ToGSAA scintigraphy
Background d
Thee asialoglycoprotein (ASGP) receptor is only present in mammalian hepatocytes and iss specific for the asialoglycoprotein. The ASGP receptor is composed of 2 subunits (humann hepatic lectins 1 and 2) and is expressed in large quantities on the hepatocyte sinusoidall surface adjoining the extracellular space of Disse 31. A significant decrease in thee expression of ASGP receptors is seen in patients with chronic liver diseases together withh serum accumulation of asialoglycoproteins 3 2 3 3. Asialoglycoprotein binds to ASGP receptorr and is subsequently transferred to the hepatic lysosomes where the receptor mediatedmediated endocytosis occurs. The liver is the only uptake site for 99mTc-GSA and it is thereforee an ideal agent for functional liver scintigraphy.
First,, technetium labeled galactosyl-neoglyoalbumin (99mTc-GNA) was developed as aa synthetic asialoglyoprotein to visualize and quantify its hepatic binding to the ASGP receptorr 34. For the clinical analysis of ASGP receptor, 99mTc-GSA was developed as ann analogue ligand of the ASGP receptor 3b. Since the ASGP receptor does not bind
too bilirubin, 99mTc-GSA scintigraphy is also effective in assessing the hepatic function in patientss with hyperbilirubinemia 35"38.
Kineticss and quantitative m e a s u r e m e n t of liver function
Similarr to HBS, dynamic " T c - G S A scintigraphy images are obtained, after an intravenous boluss of S9mTc-GSA, by a gamma camera positioned over the heart and liver region. The bloodd clearance and hepatic uptake are obtained by generating ROIs from heart and liver.. It is assumed that the ligand-receptor binding is a second-order process, in which a significantt fraction of receptor is occupied during the course of the imaging study. Forr the actual kinetics of the 99mTc-GSA receptor binding, three models are commonly applied. .
Figuree 1: Planar 99rnTc-GSA scintigraphy.
minutess r\ time
Thee hepatic uptake ratio (LHL15) and blood disappearance ratio (HH15) is calculated from the 99mTc-GSA time-activityy curves from the heart (grey) and the liver (black) (A). Blood disappearance constant (Kl) is calculatedd from the liver uptake curve, with the use of the disappearance halftime (T1/2) (B).
Figuree 2: Hepatobiliary scintigraphy with "mTc-mebrofenm SPECT in a patient with liver metastasis.
Thee CT scan (A) shows a large colorectal metastasis in liver segments 2 and 3. The matching SPECT image (B)) shows an inhomogeneous distribution of mebrofenin, with a decrease uptake in segment 2 and 3. Panel CC shows the planar dynamic hepatobiliary scintigraphy.
Figuree 3: Dynamic image of planar hepatobiliary scintigraphy (HBS).
Panell A shows an example of summed HBS image from 150-300 sec after intravenous injection of 99m
Tc-mebrofenin.. A region of interest (ROI) is drawn around the entire liver (red line). A second ROI is drawn aroundd the mediastinum (blood pool) (yellow line). A third ROI is drawn around the future remnant liver (greenn line), indicating segments 2 and 3 after extended right hemihepatectomy.
Panell B shows a blood pool corrected liver-uptake time-activity curve. The liver uptake of mebrofenin is calculatedd as an increase of blood pool corrected -'9m
Tc-mebrofenin uptake (y-axis) per minute over a time periodd of 200 sec.
Veraa et al. developed a three-compartment model of a bimolecular chemical reaction 39. Requiredd for the calculations in this model are the time-activity curves of liver and heart, thee patient's height, weight, hematocrit, and a portion of the injected dose from a blood sample.. Five independent parameters are calculated; receptor concentration, receptor affinityy (forward binding rate), hepatic plasma volume, extra hepatic plasma volume and hepaticc plasma flow.
Thee receptor concentration proved to be the most accurate index for hepatic function 40-41. AA five compartment model based on Michaelis-Menten-type kinetics for the receptor-ligand bindingg was introduced as a non-invasive approach, requiring no blood samples 4?. Blood
floww and maximal removal rate (Rmax) of 99mTc-G5A (mg/min) from plasma, is calculated fromm the time activity curve of the heart, liver and lung (background).
Mikii et al introduced a seven compartment model in which the receptor mediated endocytosiss and receptor recycling were included 43. It permits the quantative measurement off the total receptor amount (Rtot) and hepatic blood flow, without blood samples. Rtot
correlatess with the number of viable hepatocytes and can be used to assess the functional liverr mass 4 4.
Althoughh different parameters are calculated from the different kinetic models, many aree highly complex and not widely used in the context of liver surgery. Table 1 and 2 summarizess the parameters used in liver surgery and transplantation.
Thee most commonly used parameters in planar, dynamic 99mTc-GSA scintigraphy are the hepaticc uptake ratio of 99mTc-GSA (LHL15) and the blood clearance ratio (HH15) (figl). The HH155 is calculated by dividing the radioactivity of the heart ROI 15 min after the injection byy that after 3 min after injection. LHL15 is calculated by dividing the radioactivity of the liverr ROI by the radioactivity of the liver plus heart ROIs 15 min after the injection 35-45-46. Thee modified receptor index (MRI) is determined by dividing the LHL15 by the HH15 45. Too enable and improve the assessment of total and segmental liver function and functionall volume, 99mTc-GSA Single Photon Emission Computed Tomography (SPECT) wass introduced. Both static SPECT and dynamic SPECT are clinically applied 38,47"
49
.. Dynamic SPECT requires a fast rotating multidetector gamma camera, which is not availablee in every institution. Functional liver volume can be calculated from 99mTc-GSA SPECTT by the outline extraction method, in which specific cut-off values are used to automaticallyy outline the liver 38*48. The cut-off method does not take into account the regionall functional differences within the volume. Therefore, Satoh described a more precisee method for calculating functional liver volume 49. The functional liver volume was calculatedd depending on the degree of 99mTc-GSA radioactivity in each voxel. First, the voxell with maximal counts was determined. In a phantom study, it was determined that a voxell below 54% of the maximal count was regarded as a background. Voxels with counts abovee 80% of maximal were considered fully functional. The thickness of each voxel with countss above 80% of the maximum was considered as the maximal thickness (1.08). For eachh voxel between the 54% and 80%, the thickness was estimated according to the accumulatedd counts in that voxel.
Liverr uptake ratio (LUR) and liver uptake density (LUD) can be calculated from dynamic SPECTT acquisitions 50-51. LUR reflect the percentage of hepatic SPECT counts relative too the injected counts measured in the syringe, hereby calculating the dose that is incorporatedd in the liver. LUD is the liver uptake ratio divided by functional liver volume. Furthermore,, the hepatic 99mTc-GSA clearance (Ku ml/min) can be calculated by Patlak
plott analysis 47.
99m
Tc-GSAA liver scintigraphy in experimental surgical research
Postoperativee complications in patients with hilar cholangiocarcinoma can be substantial duee to impaired liver function and the necessity of extended resections52. Therefore, the preoperativee assessment of the FRL f unction is critical in these patients. Cholangiocarcinomas aree frequently associated with obstructive jaundice. Unlike ICG, 99mTc-GSA uptake is not influencedd by hyperbilirubinaemia. In a rat model of obstructive jaundice, 99mTc-GSA scintigraphyy proved to be a valuable method to evaluate liver function 37 A reduction in
thee 99rTTTc-GSA binding affinity, rather than a reduction of ASGP receptor per hepatocyte orr a decrease in number of hepatocytes, was responsible for the impaired uptake of 99fT Tc-GSAA 37. In cirrhotic patients, there is evidence that the decreased uptake of 99mTc-GSA is nott caused by a reduction in the number of ASGP receptors per hepatocyte, nor in the decreasee in affinity, but to a decrease in the number of hepatocytes 53. The mechanism of reducedd 99mTc-GSA uptake in other liver diseases such as steatosis is unknown.
Thee effect of liver regeneration and t/R injury on 99mTc-GSA uptake and ASGP receptor expressionn has been investigated in some preclinical studies 54,5S. A decrease in uptake off 99nTFc-GSA was described in the early phase after l/R injury, which correlated with increasedd hepatocellular necrosis. The decrease in uptake was followed by an increased
99m
Tc-GSAA uptake several days after l/R, which was consistent with liver regeneration. In experimentall studies there is controversial data on the expression of ASGP receptor after hepaticc injury and liver regeneration. Some studies described a decrease in surface ASGP receptorss during liver regeneration 56'57. However, Kouda et al confirmed an increase of GSAA uptake per hepatocyte suggesting a possible cellular compensation mechanism for thee loss of hepatocellular mass 58.
Clinicall use of
99mTc-GSA liver scintigraphy in liver surgery
99mTc-GSAA liver scintigraphy was developed in Japan as a non-invasive alternative to evaluatee liver function. The parameters obtained from planar 99rTTc-GSA scintigraphy, includingg the modified receptor index (MRI) and LHL15, correlated with conventional functionn tests such as antithrombin III, total and direct bilirubin, prothrombin time, ICG clearance,, Child -Pugh classification and histology (hepatic activity index (HAI) score), in cirrhoticc patients 45-59. Planar 99mTc-GSA scintigraphy was applicable for the evaluation of preoperativee and postoperative liver function 45. However, a discrepancy between ICGR15 andd 99mTc-GSA scintigraphy parameters is described in 9-20% of the patients in whomm the histologicall severity of disease is better reflected by 99mTc-GSA scintigraphy 60-61.
Multiplee studies have described the use of preoperative planar dynamic 99rnTc-GSA scintigraphyy for predicting postoperative complications 61 64. Preoperative GSA-Rmax and LHL155 proved to be reliable indicator for predicting the risk of postoperative complications inn patients with HCC and chronic liver disease 60-64. Preoperative LHL15 or GSA-Rmax was significantlyy lower in patients with major postoperative complications than in patients withh minor or no complications 6 0 6 4. Specific cut-off values were used to select patients withh a high risk of complications and patients with complications. For the LHL15, cut-off valuess of 0.90 65 and 0.875 61 are described. The cut-off values from other parameters include;; LHL15/preoperative liver volume of 0.76 36, total ASGP receptor concentration in thee FRL of 0.05 umoles61'63. Multivariate analysis revealed that LHL15 was a preoperative predictorr of postoperative complications, while ICGR 15 was not 65. Nanashima et al. comparedd 99rnToGSA scintigraphy with the ICG clearance test for selecting the extent of resectionn and predicting patient outcome 61. As describe before, a discrepancy between ICGG 15 and LHL15 was seen in 8.6% of the 140 patients. In these patients, LHL15 was betterr in predicting postoperative complications. Postoperative complications were frequentlyy observed in patients with a low LHL15 (< 0.875). However, liver failure was alsoo observed in patients with a relatively normal liver function. This was explained by the
factt that LHL15 only measured preoperative total liver function and not the function of thee FRL.
Forr a more accurate assessment of the FRL, 99mTc-GSA SPECT was introduced to estimate totall as well as segmental liver function 3 S'4 7 4 9. Preoperative 99mTc-GSA SPECT was more suitablee for predicting the remnant liver f unction than CTvolumetry38-38'48. One explanation iss the liver parenchymal damage which is seen around a tumor by mechanical compression orr compression on bile ducts 38 and/or blood vessels 56. This tumor compression has a largee impact on the regional liver function, while liver volume is maintained over a longer periodd of time. In cirrhotic tivers, advanced fibrosis is accompanied with a reduction of functionall hepatocytes and therefore liver volume obtained by CT does not represent thee hepatocyte functional mass in cirrhotic liver 6 7 On the other hand, functional volume measuredd by 99mTc-GSA SPECT, reflected the functional hepatocyte mass 49-68.
Thee outline extraction method with specific cut-off levels is frequently used to calculate thee functional hepatic volume 32,38,66,69-71 |t js based on the assumption that the liver
functionn is uniformly distributed in the tissue included within the cut off value. Especially inn tumor bearing and compromised livers, function is not distributed homogeneously. Therefore,, functional volume may not correlate with the intrinsic liver function measured withh dynamic planar GSA scintigraphy 4 6'4 9.
Too overcome this problem, dynamic SPECT was introduced. A study by Sugahara et al. demonstratedd the advantage of dynamic SPECT for the assessment of regional liver functionn 72, Liver functional volume (calculated with the cut-off method), as well as liver uptakeuptake ratio <LUR) and liver uptake density (LUD) were calculated in patients with different severityy of liver disease. Both LUR and LUD decrease with the severity of liver disease. Functionall volume however, was only significantly decreased in patients with Child-Pugh C classification.. The ratio between LUR and LUD of the left and right liver lobe changed with thee progression of liver disease, confirming that the liver function in compromised patients iss not distributed homogeneously.
Owingg to the possibility to measure the FRL function, dynamic SPECT can be used to preoperativelyy predict postoperative complications 47*49. Patients with postoperative complicationss due to liver insufficiency had significantly lower hepatic FRL 99mTc-GSA clearancee (Ku in ml/min) compared with patients without complications73. Satoh et al used
thee predictive residual index (PRI) for evaluating the FRL function before resection 49. The PRII could be used to preoperatively predict postoperative complications (positive predicting valuee 71% and negative predicting value 100% with a cut-off value of 0.38). Conclusions inn both studies however, are based on a relatively small amount of complications.
Postoperativee fiver regeneration is impaired in patients with chronic liver disease 74. Especiallyy the severity of liver fibrosis correlates with impaired regeneration. Since 99rr Tc-GSAA scintigraphy correlates with the severity of liver fibrosis, it can be used as a preoperative non-invasivee method to predict the rate of liver regeneration 75. Multiple studies have describedd a discrepancy between functional liver regeneration and volumetric regeneration. Tanakaa et al. reports that functional recovery is impaired in large resections 46. However, dataa presented in this study showed that four weeks after a resection of two or three segments,, the average LHL15 recovered to 95% of the preoperative measured value. The volumee recovered to approximately 70%. Therefore, the functional recovery is greater then
thee volumetric recovery indicating the exact opposite of the conclusions drawn by the authors. .
Kwonn et al described in two similar studies that the functional regeneration measured byy 99mTc-GSA SPECT is more rapid than the morphological regeneration measured by CT volumetryy 70'71.The functional and volumetric liver regeneration was delayed in patients withh underlying liver disease. Although, there was no direct comparison made between
99m
Tc-GSAA SPECT and CT volumetry, it was concluded that functional recovery was more rapidd in patients with injured livers. However, again the data presented in these studies doo not provide enough evidence for this conclusion. Although, 99mTc-GSA scintigraphy iss useful to assess regeneration, it is difficult to draw conclusions about the difference betweenn functional and volumetric regeneration.
Thee functional hypertrophy after PVE can be evaluated with the use of 99rnTc-GSA scintigraphyy 51-69-76.77, |n two studies, the increase of liver function assessed with dynamic
99m
Tc-GSAA SPECT was compared with morphologic hypertrophy measured with CT volumetryy after PVE in cirrhotic and non-cirrhotic patients 69'77. The increase in 99mTc-GSA uptakee (expressed in LUR, LUD, residua! functional liver volume and PR!) was more extensive thann the degree of morphologic hypertrophy after PVE. Therefore, it was concluded that
99m
TeGSAA scintigraphy was useful in evaluating the functional hypertrophy, which could nott be evaluated with CT volumetry after PVE. Patients with a small liver volume and aa low 99fTTc-GSA uptake in the non-embolized lobe after PVE had an increased risk of developingg postoperative liver failure. So far no studies,regarding the use of 99mTc-GSA scintigraphyy in selecting candidates for PVE, have been published. Therefore, further researchh in this field is warranted
Clinicall use of
99rTrTc-GSA scintigraphy in liver transplantation
Afterr liver transplantation, the graft function is affected by many factors causing acute andd chronic rejection and thus the evaluation of graft function after transplantation is of cruciall importance.
Inn a study with seven liver transplant patients, the functional reserve of liver allografts wass evaluated with 99mTc-GSA scintigraphy 78. 99mTc-GSA scintigraphy using the total amountt of ASGP receptors (Rtot as described by kinetic model of Miki) was compared with
conventionall liver function tests and histopathology evaluation of a biopsy. The histological liverr damage of the graft had a good correlation with the Rtot and even though cohort
sizee was small, the study indicates the potential utility of 99mTc-GSA scintigraphy as a noninvasivee method to evaluate graft function after transplantation.
Inn a study with thirteen patients 99mTc-GSA scintigraphy was used to monitor both the graft andd native liver function after auxiliary partial orthotopic liver transplantation (APOLT) 79. inn an APOLT procedure, the native liver is left partially in place and the donor liver graft iss positioned orthotopically. The uptake of 99mTc-GSA (calculated using the Patlak plot) wass a better predictor for the actual graft function than the conventional morphological volumee assessed by CT volumetry. Especially in patients with severely damaged liver grafts, thee 99mTc-GSA uptake corresponded better with the histopathological evaluation of liver biopsyy than CT volumetry.
Inn 2004, Kwon et al. briefly described the necessity of accurate estimation of the FRL functionn in living donor operations 80. The authors conclude that the estimated FRL functionn by GSA SPECT is useful to select the procedure of hepatectomy in the setting of livingg donors. However, this study was performed in 152 patients resected predominantly forr malignant tumors and not in LDLT procedures. Eighty-three percent of the patients were resectedd for hepatocellular carcinomas which are frequently associated with liver cirrhosis. Therefore,, it is questionable if the patients included in this study are representative for livingg donors.
Hepatobiliaryy scintigraphy with IDA analogues
Background d
99rT1
Tc-IDAA agents were introduced in 1976 by Loberg et al. 81. These lidocaine analogues aree transported to liver predominantly bound to albumin R 8 2. Dissociation between albuminn and the 99mTc-IDA agents occurs in the hepatic space of Disse, after which it iss taken up by the hepatocytes. The hepatic uptake of IDA analogues is similar to the uptakee of organic anions such as bilirubin 82. IDA agents are excreted in the bile canaliculi similarr to ICG, without undergoing biotransformation during their transport through the hepatocyte,, and are therefore ideal tracers for the biliary tract 8 1 8 3. The list of suggested bilee canalicular transporters include bile salt excretory pump and multidrug resistance proteinss -1, 2 84.
Liverr uptake of IDA agents can be affected by high plasma levels of bilirubin 85. Of all IDA analogues,, mebrofenin shows the highest hepatic uptake, minimal urinary excretion and resistss strongly the displacement by high plasma bilirubin concentration 8 5 8 6. Therefore, mebrofeninn is considered the most suitable agent for hepatic and biliary diagnostics. 99m Tc-mebrofeninn uptake can be hindered by hypoalbuminemia, as albumin is the main plasma carrierr of mebrofenin 85. Hypoalbuminemia consequently decreases hepatic delivery of mebrofeninn and increases renal excretion. Conversely, hypoalbuminemia in liver disease is aa sign of impaired liver function and therefore decreased uptake of IDA in patients with hypoalbuminemiaa can still reflect liver function under these circumstances.
Thee kinetics and quantitative measurement of liver function
Measurementt of hepatic uptake function by the clearance rate of the IDA analogue lodidaa was first described by Ekman et al. 87 After the intravenous injection of 99m Tc-mebrofenin,, a dynamic scintigraphy is obtained with the use of a gamma camera. 99rrTc mebrofeninn uptake of the liver is determined by drawing a region of interest (ROI) around thee liver, the heart (serving as blood pool) and around the total field of view (fig. 2). Three differentt time-activity curves are generated based on these ROIs. With the 3 parameters, thee hepatic 99mTomebrofenin uptake rate (%/min) can be calculated. Radioactivity values acquiredd between 150 and 350 sec post injection are used to ensure that the calculations aree made during a phase of homogenous distribution of the agent in the blood pool andd before occurrence of biliary excretion 88'89, Furthermore, ROIs can be drawn around partss of the liver to calculate regional differences in 99mTc-mebrofenin uptake (fig.2).
Thee regional uptake of mebrofenin can be assessed with a small intra- and interobserver variationn 88-90.
Alternativee methods of determining liver function are the hepatic extraction fraction, the timee at which maximal hepatic radioactivity occurs ( Tpeak), as well as the time acquired
forr peak activity to decrease by 50% (T1/2 peak) 91"93. The hepatic extraction fraction is
calculatedd by drawing ROIs around the left ventricle of the heart and the liver and is furtherr calculated from the time-activity curve by a deconvulsion analysis using the Fourier transformm method 94.
HBSS in experimental surgical research
Thee measurement of liver function in small animal models remains a challenge. Many quantitativee liver function tests require repetitive blood samples, and are therefore difficult too use in small animal models. Hepatic extraction fraction, as well as T1/2 peak measured
byy HBS is used as a non-invasive method to evaluate hepatic function after ischemia reperfusionn (l/R) injury and it is used to quantify the protective effect of new interventions onn l/R injury 9 5 9 6. The application of HBS for the measurement of liver function in small animalss was confirmed in experimental models of acute and chronic liver damage 93 97 Forr the evaluation of functional regeneration in small animals, serial measurements aree needed over a long time period. The use of the hepatic 99mTc-mebrofenin uptake ratee measured by dedicated pinhole HBS in different rat models of liver regeneration hass recently been validated 91. HBS proved to be an accurate, non-invasive tool for the measurementt of liver function in the rat, and enabled serial measurements within the samee animal91.
Clinicall use of HBS in liver surgery
99m
Tc-labeledd IDA analogues were first used in cholescintigraphy for the diagnosis of multiplee biliary diseases 82-98'99. More recently, the application of HBS has been proposed forr the assessment of liver function 1 0 .
Thee use of 99rnTc-mebrofenin HBS for the preoperative assessment of liver function in patientss undergoing liver surgery, was first described by Erdogan et al S9, In 54 patients scheduledd for liver resection, 99mTc-mebrofenin uptake assessed by HBS strongly correlated withh the ICG clearance test. HBS provided both quantitative as well as visual information aboutt total and regional liver function. The morphological information obtained from HBSS provided information on localization of liver segments with inferior function. The biliaryy excretion could be used to preoperative^ determine segmental cholestasis as well ass postoperative biliary complication such as bile leakage and biliary obstructions. These featuress make HBS a valuable liver function test in the context of liver resection.
Owingg to the possibility to determine regional liver function, HBS was validated as a tool too determine the preoperative liver functional reserve and to estimate the FRL function 88. Inn this small patient study, the preoperative estimated FRL function correlated well with thee actual remnant liver function one day after resection.
Forr a surgeon, an important aspect of a liver function test is the possibility to accurately predictt postoperative complications before partial hepatectomy. The predictive value of FRLL uptake function measured preoperatively by HBS for the short-term outcome after
partiall liver resection was investigated by Dinant et al.90. Forty-six patients with and withoutt parenchymal disease were included in this study. Preoperative measurement off FRL function by planar dynamic 99rTTc-mebrofenin HBS proved more valuable than measurementt of FRL volume by CT for the risk assessment of postoperative liver failure andd liver failure related mortality.
AA safe resection could be performed in patients with a FRL uptake above 2.5 %/min/BSA (Bodyy Surface Area), with a 3% chance of developing postoperative liver failure and liver failuree related mortality. However, in patients with a FRL uptake below 2.5 %/min/BSA, thee risk of postoperative liver failure increased to 56%.
Althoughh to date there are no studies on the use of HBS for the selection of candidates for PVE,, HBS has the ability to select patients with a high risk of postoperative liver failure 90. Furthermore,, because of the ability to measure regional liver function, HBS could possibly bee useful for the evaluation of the functional increase of the FRL after PVE.
Postoperativee liver regeneration is frequently evaluated by CT volumetry. Bennink et al. comparedd the volumetric regeneration three months after partial liver resection with the functionall regeneration measured by HBS and ICG-15 88.There was a significant correlation betweenn the ICG clearance and HBS. Only a weak association between functional liver regenerationn measured with both HBS and ICG and liver volume regeneration measured withh CT volumetry was observed. This discrepancy indicates that the functional recovery mayy be an independent mechanism in addition to the volumetric regeneration.
Recently,, 99rnTc-mebrofenin SPECT was introduced to measure functional volume 101. In aa study with 18 patients, it was demonstrate that the functional volume measured by SPECT,, correlated with the liver volume measured by CT. Furthermore, the preoperative estimatedd FRL functional volume had a strong correlation with actual postoperative functionall volume. A combination of low dose CT scan with HBS combined with SPECT, providedd accurate information on segmental liver function and enabled a more precise measurementt of FRL functional volume and function 101 (fig.3).
Clinicall use of HBS in liver transplantation
Biliaryy complications, as well as hepatic dysfunction due to graft rejection, are major causess of postoperative morbidity and mortality in liver transplant recipients. Many studies havee shown that HBS is an accurate, noninvasive technique for the diagnosis of biliary complicationss including segmental and total biliary obstruction, as well as bile leakage in bothh adult and pediatric transplanted patients 102-105.
Thee application of HBS for the detection of graft dysfunction due to rejection is unclear. Liverr biopsy is frequently used to detect graft rejection. Brunot et al. demonstrated a close relationn between early biopsy results and liver uptake function measured by HBS suggesting thee usefulness of quantitative HBS in distinguishing graft rejection from cholestasis 106. Inn contrast, others report that HBS can distinguish between normal grafts and those sufferingg from rejection and/or cholestasis, but not between biliary complications and rejectionn 102-107.
Inn heterotopic liver transplantation the native liver is left in situ, and a graft is transplantated elsewheree in the abdominal cavity^ In some patients, the native liver recovers and regains function.. Individual assessment of the graft and the native liver is difficult since most
functionn test measure total liver function. HBS has the unique ability to separate the functionall assessment of the graft from the native liver 108<109.
Owingg to the increased shortage of cadaver livers, living donor transplantation is used too expand the organ pool. In living related liver transplantation (LRLT), a left or right hepatectomyy is performed in a living donor. After transplantation, the liver has the ability too regenerate to its predetermined size. The regeneration capacity in donors after LRLT wass investigated with the use of HBS 1 1 . As described by others, this study indicates thatt acceleration of organ function is an early compensatory mechanism after reduction off organ volume 111. To date, no studies have been published on the use of HBS for the preoperativee assessment of the liver function of the donor in LRLT.
Discussion n
Currentt guidelines for safe resections are based on preoperatively determined FRL volumee by CT 28. Liver diseases such as cirrhosis, fibrosis and steatosis can affect total andd segmental liver function. Therefore, FRL volume assessed by CT volumetry can be unreliablee and unrepresentative for the actual liver function. Nuclear imaging techniques, includingg 99mTc-GSA scintigraphy and 99mTc-mebrofenin H8S are used as noninvasive quantitativee methods for evaluating total liver function as well as FRL function. Both techniquess are applicable in patients with parenchymal liver disease. This aspect forms aa growing clinical challenge as the number of patients with parenchymal liver disease is expectedd to dramatically increase in the near future due to the close connection of several parenchymall liver diseases with aspects of Western lifestyle, i.e. obesitas and sexually transmittedd diseases
HBSS is an accurate method for preoperative assessment of liver function and prediction off postoperative complications 89'90. Although dynamic HBS can be used to determine regionall liver function, planar images are not suitable for the assessment of segmental liverr function.99mTc-mebrofenin SPECT could improve the assessment of liver function on thee segmental level and enable the assessment of functional volumes.
Multiplee studies have investigated the use of preoperative 99mTc-GSA scintigraphy too determine the limits for safe resection 6 1.6V3 Liver function is expressed by many different,, sometimes complex parameters (table 1 and 2), making it difficult to compare studiess and cause extensive discrepancies of obtained data. However, there is enough evidencee indicating that 99rrTc-GSA scintigraphy is an accurate technique to select patients withh a high risk of developing postoperative liver failure.
Too date, there is no consensus on the indications for PVE 28. Although no studies have beenn performed on the application of 99mTc-GSA scintigraphy and 99mTc-mebrofenin HBS too select patients for PVE, both techniques have the capability to clarify the indications forr PVE.
Afterr PVE, hypertrophy of the non-embolized liver segments is traditionally assessed by CTT volumetry. However, a discrepancy between volumetric hypertrophy and functional increasee has been described. Some studies indicate that functional regeneration is more rapidd and of greater magnitude than the volumetric gain 69'77. However, few methods are
availablee to measure liver function of the non-embolized fiver segments. Both 99mTc-G5A scintigraphyy and 99mTc-mebrofenin H8S have the unique ability to visualize and quantify regionall liver function and can therefore be used to assess the functional increase of thee FRL after PVE. In liver transplantation, HBS and 99mTc-GSA scintigraphy are used to assesss graft function. Additionally, HBS can diagnose biliary complications after liver transplantation. .
99m
Tc-GSAA scintigraphy and 99rTTc-mebrofenin HBS are based on two different principles.
99m
Tc-GSAA scintigraphy measures the binding of 99mTc-GSA to its receptor on the hepatocyte,, and therefore it is an indirect parameter of liver function. The amount of ASGPP receptors is decreased in chronic hepatitis and liver cirrhosis. However, it is unknown iff the receptors are decreased in patients with compromised livers due to steatosis or chemotherapy.. Since 99mTc-GSA is not excreted into the bile, 99mTc- GSA scintigraphy is nott suitable to visualize the biliary system. Therefore it can not be used to diagnose biliary complicationss after liver surgery or transplantation. HBS, on the other hand, measures thee uptake and excretion of mebrofentn by the hepatocytes, and therefore has the ability visualizee the biliary system. The uptake and excretion of 99mTc-mebrofenin is similar to thatt of organic anions such as bilirubin 82. HBS is therefore a direct parameter of liver function.. The uptake of 99mTc-mebrofenin can be influenced by hepatic blood flow, hypoalbuminemiaa and high concentrations of bilirubin 85. As the hepatic uptake of many substancess is influenced by the same factors, it can still be used as a functional test under thesee conditions.
Althoughh many studies have proved the value of nuclear imaging in liver surgery and transplantation,, they are not widely used. 99mToGSA scintigraphy is used in Japan, but is not approvedd in Europe and the USA, 99mTc-mebrofenin HBS technique is relatively new, and onlyy few clinical trials have been performed. Clinical trials in larger populations are required too confirm the application of 99mTc-mebrofenin HBS for the pre-operative assessment of liverr function and postoperative evaluation of complications and regeneration.
Bothh GSA scintigraphy and HBS are simple techniques that can be implemented in everyy hospital with a nuclear medicine department. Since many conventional methods, includingg CT volumetry have limitations, additional HBS or GSA scintigraphy, can improve thee selection of patients with increased risk of postoperative complications.
Conclusion n
Owingg to the complexity of liver function, an ideal liver function test meeting all required criteriaa is yet to be discovered. Many liver function tests have limitations for the assessment off patients suitable for liver surgery. Both 99mTc-GSA scintigraphy and 99mTc-mebrofenin HBSS are noninvasive, reliable techniques that provide visual and quantitative information off both total and regional liver function. Both tests are applicable in patients with normal liverr as well as patients with a compromised liver. These features make both 99mTc-GSA scintigraphyy and 99mTc-mebrofenin HBS useful liver function tests for the application in liverr surgery and liver transplantation.
Tablee 1: Overview of parameters commonly used in dynamic planar 99mTc-GSA scintigraphy in liver surgery andd transplantation
description n
LHL155 hepatic uptake ratio Liver counts at 15 min Total liver
off 99mTc-GSA (L15) divided by the r ut \c = ^\5 function
heartt (H15)plus liver Z 1 5 + / / 1 5 Regional liver
countss at 15 min function
HH155 Blood disappearance Heart counts at 15 ratioo min (H15) divided by
heartt counts at 3 min (H3). .
MRIMRI = LHLLHL 15
HHHH 15
Totall liver function n
MRI I Modifiedd Receptor
Index x
Liverr uptake ratio (LHL15)) divided by the bloodd disappearance ratioo (HH15).
HHHH
15H3 H3
H\5 H\5 Totall liver function n KL L Bloodd disappearance constant t Calculatedd from thee liver uptake curve,, with the use off disappearance halftimee (T1/2)Totall liver liverliver uptake (t) = C„ (j - <?*') f u n c t i o n
LU15 5 Liverr uptake Cumulativee liver
uptakee from 15 to 16 minutess after injection fromm the liver time-activityy curve (L(t))
L{l)dl L{l)dl totaltotal injected dose
Totall liver function n
LHL15-VV Ratio of Liver uptake Liver uptake ratio too liver volume (LHL15) divided by
totall liver volume
10000
Total liver function n
Rmax x Maximall removal
ratee of GSA
Calculationn with the kineticc model of Ha-Kawa a
Multiplee equations Totall liver function n
RO O Asialoglycoprotein n
receptor r concentration n
Calculationn with the kineticc model of Vera, etal. .
Multiplee equations Totall liver function n
Tablee 2:
FLV V
"Tc-GSAA SPECT parameters commonly used in liver surgery and transplantation
Ku u LUR R Functionall liver volume e Hepaticc 99m Tc-GSAA clearance Liverr uptake ratio o
Outlinee extraction method withh specific cut-off level Summ of the product of the liverr surface in each slice and slicee thickness.
Patlakk plot analysis L(t)) is the liver activity, B(t)) is the blood activity, Vhh is the hepatic blood volume. .
Hepaticc SPECT counts divided byy injected syringe counts
Totall liver
^Qiversurface-xslice^Qiversurface-xslice thickness) Function Regionall liver
function n
Totall liver i(/)/«(/)=A'„„ x r\B(Tyft/fi<,) + FA Function
Regionall liver function n
Totall liver Function n
ci/unisci/unis syringe preinjvciiu
Regionall liver function n 3 3 C C n_ _
3 3
5' '
w w
< <
c c
"5 5a a
LUD D Liverr uptake
density y
Liverr uptake ratio divided by liverr functional volume
LUDLUD = - LUR LUR
FunctionalFunctional liver volume Totall liver Function n Regionall liver function n
PRI I Predictivee Sum of the product of
ki-residuall index value (blood disappearance constant)) and functional liverr volume (FLVi) in the FRL inn each slide divided by the productt of normal k-value (healthyy volunteers) and total FLV V PRIPRI =
__ YM
xFLn KnxFLV' KnxFLV' Regionall liver function n FRR R Functional l resectionn ratioCountss in the expected resectionn volume divided by thee counts in the total liver volume. .
totaltotal liver volume roiirits
Regionall liver ',(!00
function
References s
1.. Shoup M, Gonen M, O'Angelica M et al. Voiumetrtc analysis predicts hepatic dysfunction in patientss undergoing major liver resection. J Gastrointest Surg 2003; 7:325-330.
2.2. Shirabe Kt Shimada M, Gion T et al. Postoperative liver failure after major hepatic resection for hepatocellularr carcinoma in the modem era with special reference to remnant liver volume. J Amm Coll Surg 1999; 188:304-309.
3.. Makuuchi M, Thai BLr Takayasu K et al. Preoperative portal embolization to increase safety of majorr hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990; 107:521-527. .
4.. Abdalla EK, Barnett CC, Doherty D et al. Extended hepatectomy in patients with hepatobiliary malignanciess with and without preoperative portal vein embolization. Arch Surg 2002; 137:675-680. .
5.. Nagmo M, Nimura Y, Kamiya J et al. Changes in hepatic lobe volume in biliary tract cancer patientss after right portal vein embolization. Hepatology 1995; 21:434-439.
6.. Azoulay D, Castaing D, Krissat J et al. Percutaneous portal vein embolization increases the feasibilityy and safety of major liver resection for hepatocellular carcinoma in injured liver. Ann Surgg 2000; 232:665-672.
7.. Azoulay D, Castaing D, Smail A et al. Resection of nonresectable liver metastases from colorectall cancer after percutaneous portal vein embolization. Ann Surg 2000; 231:480-486. 8.. Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future
prospects.. Br J Surg 2001; 88:165-175.
9.. Farges O, Belghiti J, Kianmanesh R et al. Portal vein embolization before right hepatectomy: prospectivee clinical trial. Ann Surg 2003; 237:208-217.
10.. Yamanaka N, Okamoto E, Kawamura E et al. Dynamics of normal and injured human liver regenerationn after hepatectomy as assessed on the basis of computed tomography and liver function.. Hepatology 1993; 18:79-85.
11.. Pugh RN, Murray-Lyon IM, Dawson JL et al. Transection of the oesophagus for bleeding oesophageall varices. Br J Surg 1973; 60:646-649.
12.. Schneider PD. Preoperative assessment of liver function. Surg Clin North Am 2004; 84:355-373. .
13.. Nagashima I, Takada T, Okinaga K et al. A scoring system for the assessment of the risk of mortalityy after partial hepatectomy in patients with chronic liver dysfunction. J Hepatobiliary Pancreatt Surg 2005; 12:44-48.
14.. Lau H, Man K, Fan ST et al. Evaluation of preoperative hepatic function in patients with hepatocellularr carcinoma undergoing hepatectomy. Br J Surg 1997; 84:1255-1259.
15.. Paumgartner G, The handling of indocyanine green by the liver. Schweiz Med Wochenschr 1975;; 105:1-30.
16.. Tygstrup N. Determination of the hepatic elimination capacity (Lm) of galactose by single injection.. Scand J Clin Lab Invest Suppl 1966; 18:118-125.
17.. Ranek L, Andreasen PB, Tygstrup N. Galactose elimination capacity as a prognostic index in patientss with fulminant liver failure. Gut 1976; 17:959-964.
18.. Reichen J, Widmer T, Cotting J. Accurate prediction of death by serial determination of galactosee elimination capacity in primary biliary cirrhosis: a comparison with the Mayo model. Hepatologyy 1991; 14:504-510.
19.. Yamanaka N, Okamoto E, Toyosaka A et al. Prognostic factors after hepatectomy for hepatocellularr carcinomas. A univariate and multivariate analysis. Cancer 1990;
65:1104-1110. .
20.. Redaefli CA, Dufour JF, Wagner M et al. Preoperative galactose elimination capacity predicts complicationss and survival after hepatic resection. Ann Surg 2002; 235:77-85.
21.. Lam CM, Fan ST, Lo CM et al. Major hepatectomy for hepatocellular carcinoma in patients with ann unsatisfactory indocyanine green clearance test. Br J Surg 1999; 86:1012-1017.
22.. Oellerich M, Armstrong VW. The MEGX test: a tool for the real-time assessment of hepatic function,, Ther Drug Monit 2001; 23:81-92.
23.. Ravaioli M, Grazi GL, Principe A et al. Operative risk by the lidocaine test (MEGX) in resected patientss for HCC on cirrhosis. Hepatogastroenterology 2003; 50:1 552-1 555.
24.. Ercolani G, Grazi GL, Calliva R et al. The lidocaine (MEGX) test as an index of hepatic function: itss clinical usefulness in liver surgery. Surgery 2000; 127:464-471.
25.. Oellerich M, Armstrong VW. The MEGX test: a tool for the real-time assessment of hepatic function.. Ther Drug Monit 2001; 23:81-92.
26.. Kubota K, Makuuchi M, Kusaka K et al. Measurement of liver volume and hepatic functional reservee as a guide to decision-making in resectional surgery for hepatic tumors. Hepatotogy 1997;; 26:1176-1181.
27.. Vauthey JN, Chaoui A, Do KA et al. Standardized measurement of the future liver remnant priortoo extended liver resection: methodology and clinical associations. Surgery 2000; 127:512-519. .
28.. Clavien PA, Emond J, Vauthey JN et al. Protection of the liver during hepatic surgery. J Gastrointestt Surg 2004; 8:313-327.
29.. Lindor KD, Bru C, Jorgensen RA et al. The role of ultrasonography and automatic-needle biopsy inn outpatient percutaneous liver biopsy. Hepatology 1996; 23:1079-1083.
30.. McGill DB, Rakela J, Zinsmeister AR et al. A 21-year experience with major hemorrhage after percutaneouss liver biopsy. Gastroenterology 1990; 99:1396-1400.
31.. Akaki S, Mitsumori A, Kanazawa S et al. Technetium-99m-DTPA-galactosyl human serum albuminn liver scintigraphy evaluation of regional CT/MRI attenuation/signal intensity differences.. J Nud Med 1998; 39:529-532.
32.. Marshall JS, Green AM, Pensky J et al. Measurement of circulating desialyiated glycoproteins andd correlation with hepatocellular damage. J Clin Invest 1974; 54:555-562.
33.. Sawamura T, Kawasato S, Shiozaki Y et al. Decrease of a hepatic binding protein specific for asialoglycoproteinss with accumulation of serum asialoglycoproteins in galactosamine-treated rats.. Gastroenterology 1981; 81:527-533.
34.. Vera DR, Krohn KA, Stadalnik RC et al. Tc-99m-galactosyl-neoglycoalbumin: in vivo characterizationn of receptor-mediated binding to hepatocytes. Radiology 1984; 151:191-196. 35.. Kokudo N, Vera DR, Makuuchi M. Clinical application of TcGSA. Nud Med Biol 2003;
30:845-849. .
36.. Fujioka H, Kawashita Y, Kamohara Y et al. Utility of technetium-99m-!abe1ed-galactosyl human serumm albumin scintigraphy for estimating the hepatic functional reserve. J Clin Gastroenterol 1999;; 28:329-333.
37.. Mimura T, Hamazaki K, Sakai H et al. Evaluation of hepatic functional reserve in rats with obstructivee jaundice by asyaloglycoprotein receptor. Hepatogastroenterology 2001; 48:777-782. .
38.. Mitsumori A, Nagaya I, Kimoto S et al. Preoperative evaluation of hepatic functional reserve followingg hepatectomy by technetium-99m galactosyl human serum albumin liver scintigraphy andd computed tomography. Eur J Nucl Med 1998; 25:1377-1382.
39.. Vera DR, Stadalnik RC, Trudeau WL et al. Measurement of receptor concentration and forward-bindingg rate constant via radiopharmacokinetic modeling of technetium-99m-galactosyl-neoglycoalbumin.. J Nucl Med 1991; 32:1169-1176.
40.. Kudo M, Todo A, Ikekubo K et al. Quantitative assessment of hepatocellular function through inn vtvo radioreceptor imaging with technetium 99m galactosyl human serum albumin. Hepatologyy 1993; 17:814-819.
41.. Vera DR, Stadalnik RC, Metz CE et al. Diagnostic performance of a receptor-binding radiopharmacokineticradiopharmacokinetic model. J Nucl Med 1996; 37:160-164.
42.. Ha-Kawa SK, Tanaka Y. A quantitative model of technetium-99m-DTPA-galactosyl-HSA for the assessmentt of hepatic blood flow and hepatic binding receptor. J Nucl Med 1991; 32:2233-2240. .
43.. Miki K, Kubota K, Kokudo N et al. Asialoglycoprotein receptor and hepatic blood flow using technetium-99m-DTPA-galactosyll human serum albumin. J Nuci Med 1997; 38:1798-1807. 44.. Miki K, Kubota K, Inoue Y et al. Receptor measurements via Tc-GSA kinetic modeling are
proportionall to functional hepatocellular mass. J Nucl Med 2001; 42:733-737.
45.. Kwon AH, Ha-Kawa SK, Uetsuji S et al. Use of technetium 99m diethylenetriamine-pentaacetic acid-galactosyl-humann serum albumin liver scintigraphy in the evaluation of preoperative and postoperativee hepatic functional reserve for hepatectomy. Surgery 1995; 117:429-434. 46.. Tanaka A, Shinohara H, Hatano E et al. Perioperative changes in hepatic function as assessed
byy asialoglycoprotein receptor indices by technetium 99m galactosyl human serum albumin. Hepatogastroenterologyy 1999; 46:369-375.
47.. Hwang EH, Taki J, Shuke N et al. Preoperative assessment of residual hepatic functional reservee using 99mTc-DTPA-galactosyl-human serum albumin dynamic SPECT. J Nucl Med 1999; 40:1644-1651. .
48.. Kwon AH, Matsui Y, Ha-Kawa SK et al. Functional hepatic volume measured by technetium-99m-galactosyl-humann serum albumin liver scintigraphy: comparison between hepatocyte volumee and liver volume by computed tomography. Am J Gastroenterol 2001; 96:541-546. 49.. Satoh K, Yamamoto Y, Nishiyama Y et al. 99mTc-GSA liver dynamic SPECT for the preoperative
assessmentt of hepatectomy. Ann Nucl Med 2003; 17:61-67.
50.. Onodera Y, Takahashi K, Togashi T et al. Clinical assessment of hepatic functional reserve usingg 99mTc DTPA galactosyl human serum albumin SPECT to prognosticate chronic hepatic diseases-validationn of the use of SPECT and a new indicator. Ann Nucl Med 2003; 17:181-188. .
51.. Sugai Y, Komatani A, Hosoya T et al. Response to percutaneous transhepatic portal embolization: neww proposed parameters by 99mTc-GSA SPECT and their usefulness in prognostic estimation afterr hepatectomy. J Nucl Med 2000; 41:421-425.
52.. NaginoM, Kamiya J, Uesaka Ketal. Complications of hepatectomy for hilar cholangiocarcinoma. Worldd J Surg 2001, 25:1277-1283.
53.. Kawasaki S, Imamura H, Bandai Y et al. Direct evidence for the intact hepatocyte theory in patientss with liver cirrhosis. Gastroenterology 1992; 102:1351-1355.
54.. Kwon AH, Inoue T, Ha-Kawa SK. Characterization of the asialoglycoprotein receptor under hypoxicc conditions in primary cultured rat hepatocytes. J Nucl Med 2005; 46:321-325. 55.. Toyama H, Suzuki K, Naito A et al. Evaluation of asialoglycoprotein receptor imaging agent
ass a marker of hepatic ischemia-reperfusion injury and recovery. Ann Nucl Med 1999; 13:155-160. .
56.. Hirose S, Ise H, Uchiyama M et al. Regulation of asialoglycoprotein receptor expression in the proliferativee state of hepatocytes. Biochem Biophys Res Commun 2001; 287:675-681. 57.. Howard DJ, Stocked RJ, Morell AG. Asialoglycoprotein receptors in hepatic regeneration. J Biol
Chemm 1982; 257:2856-2858.
58.. Kouda K, Ha-Kawa SK, Tanaka Y. Increased technetium-99m-GSA uptake per hepatocyte in ratss with administration of dimethylnitrosamine or hepatocyte growth factor. J Nucl Med 1998;39:1463-1467. .
59.. Sasaki N, Shiomi S, Iwata Y et al. Clinical usefulness of scintigraphy with 99mTc-galactosyl-humann serum albumin for prognosis of cirrhosis of the liver. J Nucl Med 1999; 40:1652-1656. 60.. Kwon AH, Ha-Kawa SK, Uetsuji S et al. Preoperative determination of the surgical procedure forr hepatectomy using technetium-99m-gaiactosyl human serum albumin (99mTc-GSA) liver scintigraphy.. Hepatology 1997; 25:426-429.
61.. Nanashima A, Yamaguchi H, Shibasaki Setal. Relationship between indocyanine green test and technetium-99mm galactosyl serum albumin scintigraphy in patients scheduled for hepatectomy: Clinicall evaluation and patient outcome. Hepatol Res 2004; 28:184-190.
62.. Kim YK, Nakano H, Yamaguchi M et al. Prediction of postoperative decompensated liver functionn by technetium-99m galactosyl-human serum albumin liver scintigraphy in patients withh hepatocellular carcinoma complicating chronic liver disease. Br J Surg 1997; 84:793-796. 63.. Kokudo N, Vera DR, Tada K et al. Predictors of successful hepatic resection: prognostic
usefulnesss of hepatic asialoglycoprotein receptor analysis. World J Surg 2002; 26:1342-1347. 64.. Takeuchi S, Nakano H, Kim YK et al. Predicting survival and post-operative complications with Tc-GSAA liver scintigraphy in hepatocellular carcinoma. Hepatogastroenterology 1999;
46:1855-1861. .
65.. Kim YK, Nakano H, Yamaguchi M et al. Prediction of postoperative decompensated liver functionn by technetium-99m galactosyl-human serum albumin liver scintigraphy in patients withh hepatocellular carcinoma complicating chronic liver disease. Br J Surg 1997; 84:793-796. 66.. Akaki S, Okumura Y, Sasai N et al. Hepatectomy simulation discrepancy between radionuclide receptorr imaging and CT volumetry: influence of decreased unilateral portal venous flow. Ann Nucll Med 2003; 17:23-29.
67.. Imamura H, Kawasaki S, Shiga J et al. Quantitative evaluation of parenchymal liver cell volume andd total hepatocyte number in cirrhotic patients, Hepatology 1991; 14:448-453.
68.. Wu J, Ishikawa N, Takeda T et al. The functional hepatic volume assessed by 99mTc-GSA hepaticc scintigraphy. Ann Nucl Med 1995; 9:229-235.
69.. Hirai I, Kimura W, Fuse A et al. Evaluation of preoperative portal embolization for safe hepatectomy,, with special reference to assessment of nonembolized lobe function with 99mTc-GSAA SPECT scintigraphy. Surgery 2003; 133:495-506.
70.. Kwon AH, Matsui Y, Ha-Kawa SK et al. Functional hepatic volume measured by technetium-99m-galactosy!-humann serum albumin liver scintigraphy: comparison between hepatocyte volumee and liver volume by computed tomography. Am J Gastroenterol 2001; 96:541-546. 71.. Kwon AH, Matsui Y, Kaibori M et al. Functional hepatic regeneration following hepatectomy
usingg galactosyl-human serum albumin liver scintigraphy. Transplant Proc 2004; 36:2257-2260. .
72.. Sugahara K, Togashi H, Takahashi K et al. Separate analysis of asialoglycoprotein receptors in thee right and left hepatic lobes using Tc-GSA SPECT. Hepatology 2003; 38:1401-1409. 73.. Hwang EH, Taki J, Shuke N et al. Preoperative assessment of residual hepatic functional
reservee using 99mTc-DTPA-galactosyl-human serum albumin dynamic SPECT. J Nucl Med 1999; 40:1644-1651. .
74.. Koniaris LG, McKillop IH, Schwartz SI et al. Liver regeneration. J Am Coll Surg 2003; 197:634-659. .
75.. Iguchi T, Sato S, Kouno Y et al. Comparison of Tc-99m-GSA scintigraphy with hepatic fibrosis andd regeneration in patients with hepatectomy. Ann Nucl Med 2003; 17:227-233.
76.. Kubo S, Shiomi S, Tanaka H et al. Evaluation of the effect of portal vein embolization on liver functionn by {99m)tc-galactosyl human serum albumin scintigraphy. J Surg Res 2002;
107:113-118. .
77.. Nishiyama Y, Yamamoto Y, Hino I et al. 99mTc galactosyl human serum albumin liver dynamic SPETT for pre-operative assessment of hepatectomy in relation to percutaneous transhepatic porta!! embolization. Nucl Med Commun 2003; 24:809-817.
78.. Kita Y, Miki K, Hirao S et al. Liver allograft functional reserve estimated by total asialoglycoprotein receptorr amount using Tc-GSA liver scintigraphy. Transplant Proc 1998; 30:3277-3278. 79.. Sakahara H, Kiuchi T, Nishizawa S et al. Asialoglycoprotein receptor scintigraphy in evaluation
off auxiliary partial orthotopic liver transplantation. J Nucl Med 1999; 40:1463-1467.
80.. Kwon AH, Matsui Y, Kaibori M et al. Safety of hepatectomy for living donors as evaluated usingg asialoscintigraphy. Transplant Proc 2004; 36:2239-2242.
81.. Loberg MD, Cooper M, Harvey E et al. Development of new radiopharmaceuticals based on N-substitutionn of iminodiacetic acid. J Nucl Med 1976; 17:633-638.
82.. Krishnamurthy S, Krishnamurthy GT. Technetium-99m-iminodiacetic acid organic anions: review off biokinetics and clinical application in hepatology. Hepatology 1989; 9:139-153.
83.. Trauner M, Meier PJ, Boyer JL Molecular pathogenesis of cholestasis. N Eng! J Med 1998; 339:1217-1227. .
84.. Hendrikse NH, Kuipers F, Meijer C et al. In vivo imaging of hepatobiliary transport function mediatedd by multidrug resistance associated protein and P-glycoprotein. Cancer Chemother Pharmacoll 2004; 54:131-138.
85.. Krishnamurthy GT, Krishnamurthy S. Nuclear Hepatology;a textbook of hepatobiliary diseases. Berlinn Heidelberg New York: Springer, 2000.
86.. Lan JA, Chervu LR, Johansen KL et al. Uptake of technetium 99m hepatobiliary imaging agents byy cultured rat hepatocytes. Gastroenterology 1988; 95:1625-1631.
87.. Ekman M, Fjalling M, Holmberg S et al. IODIDA clearance rate: a method for measuring hepatocytee uptake function. Transplant Proc 1992; 24:387-388.
88.. Bennink RJ, Dinant S, Erdogan D et al. Preoperative assessment of postoperative remnant liver functionn using hepatobiliary scintigraphy. J Nucl Med 2004; 45:965-971.
89.. Erdogan D, Heijnen BH, Bennink RJ et al. Preoperative assessment of liver function: a comparisonn of 99mTc-Mebrofenin scintigraphy with indocyanine green clearance test. Liver Int 2004;24:117-123. .
90.. Dinant S, de Graaf W, .Verwer BJ et al. Risk Assessment of Posthepatectomy Liver Failure using Hepatobiliaryy Scintigraphy and CT-volumetry . submitted 2006.
91.. Bennink RJ, Vetelainen R, de BK et al. Imaging of liver function with dedicated animal dynamic pinholee scintigraphy in rats. Nucl Med Commun 2005; 26:1005-1012.
92.. Karamanlioglu B, Yuksel M, Temiz E et al. Hepatobiliary scintigraphy for evaluating the hepatotoxicc effect of halothane and the protective effect of catechin in comparison with histo-chemicall analysis of liver tissue. Nucl Med Commun 2002; 23:53-59.
93.. Malhi H, Bhargava KK, Afriyie MO et al. 99mTc-mebrofenin scintigraphy for evaluating liver diseasee in a rat model of Wilson's disease. J Nucl Med 2002; 43:246-252.
94.. Brown PHr Juni JE, Lieberman DA et al. Hepatocyte versus biliary disease: a distinction by deconvolutionall analysis of technetium-99m IDA time-activity curves. J Nucl Med 1988; 29:623-630. .
95.. Chavez-Cartaya R, Ramirez P, Fuente T et al. Blood clearance of 99mTc-trimethyl-Br-IDA discriminatess between different degrees of severe liver ischaemia-reperfusion injury in the rat. Eurr Surg Res 1997; 29:346-355.
96.. Yuksel M, Hatipoglu A, Temiz E et al. The role of hepatobiliary scintigraphy in the evaluation of thee protective effects of dimethylsulphoxide in ischaemic/reperfusion injury of liver. Nucl Med Communn 2000; 21:775-780.
97.. Vetelainen RL, Bennink RJ, de BK et al. Hepatobiliary function assessed by( 99m)Tc-mebrofenin cholescintigraphyy in the evaluation of severity of steatosis in a rat model. Eur J Nucl Med Mol Imagingg 2006.
98.. Krishnamurthy GT, Lieberman DA, Brar HS. Detection, localization, and quantitation of degree off common bile duct obstruction by scintigraphy. J Nucl Med 1985; 26:726-735.
99.. Krishnamurthy S, Krishnamurthy GT, Lieberman D et al. Scintigraphic criteria for the diagnosis off obstructive hepatobiliary diseases with Tc-99m IDA. Clin Nucl Med 1988; 13:704-709. 100.. Heyman S. Hepatobiliary scintigraphy as a liver function test. J Nucl Med 1994; 35:436-437. 101.. de Graaf W, Bennink RJ, van Lienden KP, van Gulik TM. Assessment of the future
remnantt liver before partial liver resection: A comparison between liver volume andd function measured by hepatobiliary scintigraphy. Eur.Surg.Res. 38. 2006. Reff Type: Abstract
102.102. Kim JS, Moon DH, Lee SG et al. The usefulness of hepatobiliary scintigraphy in the diagnosis off complications after adult-to-adult living donor liver transplantation. Eur J Nucl Med Mol Imagingg 2002; 29:473-479.
103.. Kurzawinski TR, Selves L, Farouk M et al. Prospective study of hepatobiliary scintigraphy and endoscopicc cholangiography for the detection of early biliary complications after orthotopic liverr transplantation. Br J Surg 1997; 84:620-623.
104.. Mochizuki T, Tauxe WN, Dobkin J et al. Detection of complications after liver transplantation byy technetium-99m mebrofenin hepatobiliary scintigraphy. Ann Nucl Med 1991; 5:103-107. 105.. Gelfand MJ, Smith HS, Ryckman FC et al. Hepatobiliary scintigraphy in pediatric liver transplant
recipients.. Clin Nucl Med 1992; 17:542-549.
106.. Brunot B, Petras 5, Germain P et al. Biopsy and quantitative hepatobiliary scintigraphy in the evaluationn of liver transplantation. J Nucl Med 1994; 35:1321-1327.
107.. Engeler CM, Kuni CC, Nakhleh R et al. Liver transplant rejection and cholestasis: comparison off technetium 99m-diisopropyl iminodiacetic acid hepatobiliary imaging with liver biopsy. Eur J Nucll Med 1992; 19:865-870.
108.. Buyck D, Bonnin F, Bernuau J et al. Auxiliary liver transplantation in patients with fulminant hepaticc failure: hepatobiliary scintigraphic follow-up. Eur J Nucl Med 1997; 24:138-142. 109.. Gencoglu E, Karakayali H, Moray G et at. Evaluation of pediatric liver transplant recipients using
quantitativee hepatobiliary scintigraphy. Transplant Proc 2002; 34:2160-2162.
110.. Aktas A, Koyuncu A, Yalcin H. Acceleration of hepatobiliary dynamics in liver transplant donors. Transplantt Proc 2004; 36:206-209.
111.. Aktas A, Koyuncu A, Yalcin H. Acceleration of hepatobiliary dynamics in liver transplant donors. Transplantt Proc 2004; 36:206-209.
