Quantitative liver-spleen scan using single photon emission computerized tomography (SPECT) for assessment of hepatic function in cirrhotic patients

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1 Journal of Hepatology 39 (2003) Quantitative liver-spleen scan using single photon emission computerized tomography (SPECT) for assessment of hepatic function in cirrhotic patients Eli Zuckerman 1, *, Gleb Slobodin 1, Edmond Sabo 2, Daniel Yeshurun 1, Jochanan E. Naschitz 1, David Groshar 3 1 Liver Unit, Department of Internal medicine A, Bnai Zion Medical Center, 47 Golomb Street, P.O. Box 4940, Haifa 31048, Israel 2 Department of Pathology, Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel 3 Department of Nuclear Medicine, Bnai Zion Medical Center, 47 Golomb Street, P.O. Box 4940, Haifa 31048, Israel Background/Aims: Accurate quantitative determination of liver function is critical in cirrhotic patients in order to predict outcome, particularly in patients who undergo hepatic resection or non-hepatic surgery. As colloid uptake by perfused Kupffer cells is proportional to perfused hepatocyte mass, quantitative liver spleen scan may be used as an index of perfused hepatocyte mass. Thus, this study was conducted to evaluate quantitative single photon emission computerized tomography (SPECT) of Tc-99mm-phytate colloid uptake by the liver as a test for hepatic function in cirrhotic patients. Methods: Quantitative SPECT was used to measure liver volume, quantitative colloid uptake by the liver and percentage of injected dose/ml of liver tissue in cirrhotic patients (n 5 75), non-cirrhotic patients with chronic liver disease (n 5 52) and patients without liver disease (n 5 36). Results: Although liver volume was similar among the three groups, the cirrhotic patients had significantly lower total quantitative uptake and quantitative uptake/ml compared to groups 2 and 3 (P <0.001). Quantitative liver uptake in the cirrhotic patients was highly correlated with Child-Pugh score (r , P < ) and with indocyanine green retention at 15 min (r , P < ). Conclusions: Quantitative SPECT of the liver may be an additional, useful, non-invasive quantitative test for assessment of hepatic function and severity of liver disease in cirrhotic patients. q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Liver; Single photon emission computerized tomography; Cirrhotic patients 1. Introduction Assessment of hepatic functional reserve of patients with cirrhosis is critical in order to predict prognosis, postoperative outcome in those who are candidates for nonhepatic surgery or liver resection for hepato-cellular carcinoma (HCC), or to determine the timing for liver transplantation in patients with advanced cirrhosis. Clinical assessment of liver function is based on the Child-Pugh scoring [1]. However, a considerable number of Child-Pugh class A cirrhotic patients with HCC or those who undergo Received 3 October 2002; received in revised form 12 May 2003; accepted 27 May 2003 * Corresponding author. Tel.: þ ; fax: þ address: zuckerman@b-zion.org.il (E. Zuckerman). non-hepatic surgery develop post-operative liver failure [2 4]. An accurate preoperative quantitative assessment of the hepatic functional reserve may suggest that surgery is contra-indicated in these patients. Quantitative tests of hepatic function are thought to assess the functional hepatic mass by measuring the blood flow-dependent hepatocyte function, such as indocyanine green (ICG) clearance [5 9], lidocaine clearance [10] and galactose elimination capacity [11], or blood flow-independent hepatocyte functional capacity, such as aminopyrine breath test [12,13]. However, they have their limitations and in fact, there is no single gold standard test to assess hepatic functional reserve. The blood flow-dependent quantitative liver function tests measure the perfused hepatocyte mass. An alternative strategy would be to measure the Kupffer cell mass. Because the extraction /03/$30.00 q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /s (03)

2 E. Zuckerman et al. / Journal of Hepatology 39 (2003) capacity of the individual Kupffer cell is excellent [14] and perfusion of hepatocytes and Kupffer cells is similar [15], sulfur colloid uptake by the liver reflects the perfused Kupffer cell mass which is proportional to perfused hepatocyte mass. Thus, quantitative liver spleen scan may be an excellent test for perfused hepatocyte mass. The distribution of radiocolloid uptake in the liver, spleen and bone marrow has been shown to correlate well with severity of liver disease, extent of hepatic fibrosis, prognosis, and liver function [16 19]. Quantitation of relative distribution of radiocolloid by the liver and spleen has been reported using planar and single photon emission computerized tomography (SPECT) techniques [17 21]. The ability to quantitate individual organ volume and radiopharmaceutical concentration with SPECT [22,23] led us to assess quantitative SPECT (QSPECT) of Tc-99mphytate colloid uptake by the liver as a test for hepatic function. In our previous study, QSPECT showed to be a useful method in distinguishing normal from cirrhotic livers [24]. Cirrhotic patients showed a significant decrease in quantitative liver uptake and an increase in total spleen uptake of Tc-99-phytate compared with normal controls. The decrease in liver uptake was caused by a significant decrease in %ID/ml of liver tissue without significant change in liver volume, possibly indicating liver dysfunction due to depletion of functional Kupffer cells. In the present study, QSPECT parameters were correlated not only to the Child-Pugh s score but to the ICG retention rate at 15 min (ICG-R15) which is one of the most valuable quantitative test for hepatic functional reserve in patients with chronic liver disease [2,4,8,9,25 30]. 2. Patients and methods 2.1. Patients Tc-99m-phytate-colloid QSPECT study of the liver was performed from April 1st 2000, till September 30, 2001, in 75 consecutive cirrhotic patients attending the Liver Unit at Bnai Zion Medical Center, Haifa, Israel. Some patients from this group participated in a previously reported clinical trial [24]. The clinical evaluation included routine blood tests and determination of Child-Pugh classification based on a scale of 1 through 3 for ascites (none, easily treated, refractory); bilirubin (,2, 2 2.9, $3 mg/dl); albumin (.3.5, ,,2.8 g/dl); prothrombin time (.75%, 50 75%,,50%) and hepatic encephalopathy (none, mild, severe). According to this classification, 44 patients were in Child-Pugh s class A (score 5 7), 25 were in class B (score 8 10) and six were in class C (score 11 15). In 61 of the 75 cirrhotic patients, liver biopsy confirmed the diagnosis of cirrhosis. In the other 14 patients, diagnosis of liver cirrhosis was based on clinical parameters as biopsy was avoided due to significant coagulopathy. The etiology of cirrhosis was hepatitis C virus (HCV) in 42 patients, hepatitis B virus (HBV) in 12, alcoholic liver disease (ALD) in 8, primary biliary cirrhosis (PBC) in 5, autoimmune hepatitis (AIH) in 3 and other causes in five patients. In addition, two control groups were studies: control group 1 consisted of 52 patients with chronic liver disease (CLD) without cirrhosis The absence of cirrhosis was determined by clinical parameters and liver biopsy in all 52 patients. The stage of fibrosis in this group was assessed as follows: 0, no-fibrosis; 1, portal fibrosis without septa; 2, portal fibrosis with few septa; and 3, portal fibrosis with numerous septa. The etiology of liver disease in this group was HCV in 30 patients, HBV in 5, ALD in 5, PBC in 7, AIH in 3 and Wilson s disease in 2. The second control group, the same control group from a previous study (control group 2), consisted of 36 patients without liver disease and with normal liver function tests. In this group, Tc-99m-phytate-colloid scintigraphy was performed as part of the work-up of liver space-occupying lesion. None of these patients had history or clinical evidence of liver disease, and all had a normal liver-spleen scan read by an expert in nuclear medicine and a single focal defect of less than 2 cm present or suspected in other imaging modality (liver hemangioma in most patients). The demographics and clinical characteristics of all three groups are depicted in Table 1. All studies were clinically indicated and our standardized routine liver and spleen planar scintigraphy protocol was performed with the addition of the QSPECT. The QSPECT parameters were correlated with the Child-Pugh s score in the cirrhotic patients and with ICG-R15 in both groups of patients with chronic liver disease. ICG- R15 test was not performed in patients without liver disease. A written informed consent was obtained from each patient and the study was approved by the Institutional Review Board of the Bnai Zion Medical Center SPECT technique Patients were injected with 4 5 mci ( MBq) of Tc-Phytate (Soreq NRC-Radiopharmaceuticals, Yavne, Israel) and QSPECT performed 30 min later. No patient preparation is required for the study. The exact dose injected was obtained by measuring the syringe in a dose calibrator before and after injection. The amount of radioactivity was corrected for decay from the time of preparation to the time the study was actually performed. For data acquisition a rotating gamma camera and an all-purpose, low energy collimator was used (Elcint Apex 415-ECT, Haifa, Israel). Data acquisition lasted 20 min and required 120 projections. Raw data were reconstructed by back projection with a Hann filter with a cutoff point of 0.5 cycle/cm. After reconstruction, each image was sectioned at 1- pixel (0.68-cm) intervals in the transaxial, coronal and sagittal planes using a byte matrix. Volumes and radioactive concentration measurements were calculated on the coronal reconstruction data using Front s threshold method [22,23]. Threshold is the most used method for organ or tumor segmentation in SPECT studies [31 34]. We use a simple, empirical method to measure volume and radiopharmaceutical concentration based on a fixed threshold to discern between background and target pixels [22,23]. After performing a series of phantom measurements using volumes of 30 ml to 3800 ml and concentrations between 0.01 and 3.6 Ci/ml, a threshold value of 43% of the maximal pixel activity was found to be optimal for Tc-99m [23]. When other equipment or other reconstruction algorithms are used, the threshold value and SPECT values of phantom concentrations used for conversion of count/voxel to mci/ml should first be evaluated and a series of phantom measurements as previously reported should be performed. The operator chooses the slice to define the organ and draw a region of interest (ROI) around it. The appropriateness of the ROI was checked for all frames to allow correct separation between the liver and spleen. For volume measurements (ml) the number of pixels containing activity greater than the threshold in all checked sections multiplied by the slice thickness was summed. For concentration measurements, the threshold value was subtracted from all pixels in the ROI in all checked slices. All the nonzero pixels that have higher counts than the threshold value were used to calculate the concentration. Counts/voxel were converted into concentration units (mci/ml) using the regression line obtained previously by phantom measurements [23]. The percentage of injected dose per ml of liver and spleen tissue (%ID/ml) was calculated using this value corrected for radioactivity decay. Liver and spleen uptake was then obtained by multiplying volume (ml) and %ID/ml. Thus, for each participant, six QSPECT parameters were obtained: 1, liver volume (ml) (LV); 2, quantitative liver uptake of Tc-99m-phytate-colloid (percentage of injected dose) (QLU); 3, the percentage of injected dose per milliliter of liver tissue (%ID/ml); 4, spleen volume (ml) (SV); 5, quantitative spleen uptake of Tc- 99m-phytate-colloid (percentage of injected dose) (QSU); and 6, the percentage of injected dose per milliliter of spleen tissue (%ID/ml) 2.3. ICG Test ICG (0.5 mg/kg of body weight) was given via a peripheral vein. Samples of venous blood were taken before and 15 min after the injection. From each sample, 1.0 ml of plasma was diluted with 3.0 ml of saline, and

3 328 E. Zuckerman et al. / Journal of Hepatology 39 (2003) Table 1 Demographics and clinical characteristics of study groups Cirrhosis (n ¼ 75) Non-cirrhotics (n ¼ 52) Healthy controls (n ¼ 36) Age (years) 62.2 ^ 11.5 (24 80) 56 ^ 15 (18 75) 58.7 ^ 16 (18 84) Gender (male/female) 46/29 29/23 21/15 Child-Pugh score 7.1 ^ 2.05 ALT (U/l) 45 (20 253) 49 (9 331) 24 (17 46) Albumin (g/dl) 3.3 ^ ^ ^ 0.26 PT (%) 65 (25 100) 96 (68 100) 98 (87 110) Bilirubin (mg/dl) 1 ( ) 0.7 ( ) 0.8 ( ) ALT, alanine aminitransferase; PT, prothrombin time; the values shown for age, Child-Pugh score and albumin level are means ^ standard deviation. Values for ALT, PT and bilirubin are medians. In parentheses, the range. the specimens were analyzed for ICG concentration in a spectrophotometer at 805 nm. Retention value of less than 10% at 15 min is considered to be within normal limits [35] Statistical analysis The distributions of all variables were tested for normality using the Kolmogorov Smirnov goodness of fit test. All continuous variables except ICG-R15 values in the cirrhotics were normally distributed. Comparison of radionuclide imaging-associated variables (i.e. LV, QLU, SV, QSU and %ID/ml for liver and spleen tissue) between the three groups and comparison of ICG-R15 between different stages of fibrosis in noncirrhotic patients were performed using the one-way analysis of variance test followed by the Bonferroni post-hoc test. Comparison of the ICG-R15 values between cirrhotic and non-cirrhotic patients was performed using the Mann Whitney U-test. Comparison of liver uptake between high and low fibrosis stage in the non cirrhotics, were performed using the Student s t-test for independent groups. Equality of variances was analyzed using the Levene s test. Correlation between parametric variables was tested using the Pearson s r Coefficient of correlation. Non-parametric variables were correlated using the Spearman s coefficient of correlation. Linear regression lines were drawn using the least square error method. Best cutoff liver uptake values discriminating between ICG R15 $15% and ICG R15,15% as well as between low-moderate and high fibrosis stage were calculated using the receiver operating characteristic (ROC) curve analysis. The significance of best cutoff points was tested using the Chi Square test or Fisher s exact test as appropriate. Two tailed p values of 0.05 or less, were considered to be statistically significant. 3. Results Table 2 summarizes the results of the SPECT studies. LV was not significantly different between the three groups. However, in the Child-Pugh s class C patients (n ¼ 6), the LV was significantly smaller (1163 ^ 260 ml) compared to the Child-Pugh s class A (n ¼ 44) (1550 ^ 353 ml, P ¼ 0:013) and class B patients (n ¼ 25) (1432 ^ 452 ml) (P ¼ 0:07) and compared to the non-cirrhotic patients (P ¼ 0:01). In contrast to liver volume, the QLU was significantly decreased in the cirrhotic patients compared to the noncirrhotic patients and healthy controls (P, 0:001), although there was an overlap of uptake values between the three groups (Fig. 1). The QLU was also significantly decreased in the non-cirrhotic patients compared to the healthy controls (P, 0:001). Interestingly, QLU was significantly lower in noncirrhotic patients with advanced fibrotic stage (stage 3, n ¼ 9) than those without (n ¼ 9) or low fibrosis score (stages 1 2, n ¼ 34): 37.5 ^ 6.2 versus 49.3 ^ 6.5%, respectively (P, 0:001) (Fig. 1). Using the ROC curve analysis, the best cutoff value of quantitative liver uptake to distinguish patients with high and low fibrosis score was uptake # 45.3% with sensitivity of 100% and specificity of 65.6%. (i.e. none of the patients with advanced fibrosis had liver uptake higher than 45.3%). The area under the ROC curve was 0.89 (95% confidence interval ). The %ID/ml of liver tissue, was significantly decreased in the cirrhotic group compared with the non-cirrhotics and the healthy controls (P, 0:0001). Uptake in the spleen was significantly higher in the cirrhotic patients compared to the non-cirrhotics and healthy controls (P, 0:0001) due to an increased volume, (P, 0:0001). The %ID/ml of spleen tissue was similar among the three groups (P ¼ 0:9). In the cirrhotic patients, spleen volume was inversely correlated Table 2 Liver and spleen quantitative SPECT results Cirrhosis (n ¼ 75) Non-cirrhotics (n ¼ 52) Healthy controls (n ¼ 36) P value Liver volume (ml) 1480 ^ 394 (1384, 1590) 1594 ^ 348 (1491, 1698) 1467 ^ 348 (1351, 1586) 0.21 Quantitative liver uptake (%) 35.1 ^ 13.5 (32, 39) 49.4 ^ 10 (46, 52) 61.6 ^ 10.2 (58, 65) P, %ID/ml (liver) ^ 0.01 (0.022, 0.027) ^ 0.01 (0.029, 0.035) ^ (0.039, 0.049) P, Spleen volume (ml) 839 ^ 458 (207, 2429) 395 ^ 131 (231, 781) 239 ^ 90 (208, 269) P, Quantitative spleen uptake (%) 24.7 ^ 11.8 (5.5, 61) ^ 4.4 (5, 22) 7.6 ^ 3.2 (6, 9) P, %ID/ml (spleen) ^ 0.01 (0.008, 0.076) ^ 0.01 (0.029, 0.035) ^ 0.01 (0.029, 0.035) 0.9 Quantitative liver uptake is expressed as percentage of injected dose of Tc-99m-phytate-colloid. %ID/ml: the percentage of injected dose per milliliter of liver tissue. The values shown are means ^ standard deviation. In parentheses, 95% confidence interval for the mean.

4 E. Zuckerman et al. / Journal of Hepatology 39 (2003) Fig. 1. Quantitative liver uptake as measured by SPECT of the liver in the three groups: individuals without liver disease ( normals ), non-cirrhotic patients with chronic liver disease and cirrhotic patients. Liver uptake in three sub-groups of non-cirrhotic patients is shown: patients without fibrosis (stage 0), with low (stages 1 2) and high (stage 3) fibrosis score. The horizontal lines represent the means. % of ID: percentage of injected dose of Tc- 99m-phytate colloid. with QLU (r ¼ 20:59, P, 0:0001) and with %ID/ml of liver tissue (r ¼ 20:58, P, 0:0001) but not with LV. The results of ICG studies are depicted in Fig. 2. The median ICG-R15 in the cirrhotic group was significantly higher than the ICG-R15 in the non-cirrhotic patients: 18% (range: 8 45%) versus 10% (range: 6 21%) (P, 0:0001) (Fig. 2A). IGC-R15 was higher in non-cirrhotics with advanced fibrotic stage (stage 3) than those without or low fibrosis score (stages 1 2): 12.9 ^ 2.3 versus 8.3 ^ 2 and 10.9 ^ 3.3%, respectively (P ¼ 0:008) (Fig. 2B). QLU was inversely correlated with Child-Pugh s score (r ¼ 20:64, P, 0:0001) (Fig. 3) and was significantly lower in Child-Pugh class C than class B or class A patients (P ¼ 0:013) (Fig. 4). Even a better inverse correlation was found between QLU and ICG-R15 (r ¼ 20:84, P, 0:0001) (Fig. 5). A slightly weaker correlation was also found between Child-Pugh s score and ICG R15 (r ¼ 0:74, P, 0:0001) (Fig. 6). Using the ROC curve analysis (Fig. 7), the best cutoff value of quantitative liver uptake for discriminating patients with ICG R15 $15% and ICG R15,15% was uptake of 33.3% with sensitivity of 80% (95% confidence interval: 65 90%) and specificity of 100% (95% CI: %) (P, 0:0001). The area under the ROC curve was 0.96 (95% CI ). Fig. 2. (A) ICG retention rates (percentage of total injected ICG dose) at 15 min in the non-cirrhotic and cirrhotic patients. The horizontal lines represent the medians. (B) ICG retention rates (percentage of total injected ICG dose) at 15 min for the different stages of fibrosis in three sub-groups of non-cirrhotic patients is shown: patients without fibrosis (stage 0), with low (stages 1 2) and high (stage 3) fibrosis score. The horizontal lines represent the means. Fig. 3. Correlation between Child-Pugh s score and quantitative liver uptake as measured by SPECT of the liver in the cirrhotic patients. % of ID: percentage of injected dose of Tc-99m-phytate colloid.

5 330 E. Zuckerman et al. / Journal of Hepatology 39 (2003) Fig. 4. Quantitative liver uptake as measured by SPECT of the liver in cirrhotic patients with different stages of disease defined by Child- Pugh s classification. The horizontal lines represent the means. % of ID: percentage of injected dose of Tc-99m-phytate colloid. CP, Child- Pugh. 4. Discussion In liver cirrhosis, both hepatocytes and Kupffer cells are affected equally by the fibrotic process [17 19,36]. Hoefs et al., showed that Kupffer cell mass, as determined by the relative hepatic and splenic uptake of the radiocolloid, correlates with disease severity and hepatic function in cirrhotic patients [17 19]. They also implied that radioactive colloid distribution have out-performed other tests in assessing liver disease severity [17 19,37]. There are, theoretically, several advantages in obtaining separate liver and spleen quantitation rather the simpler relative quantitation that merely determines the fractional distribution of radiocolloid between the liver and spleen (liver-spleen ratio). Some patients may have no spleen and the method could be used to evaluate the individual liver uptake of radiocolloid. It also may be useful in the follow-up of patients when the relative uptake may remain unchanged but the disease may progress or improve. Fig. 6. Correlation between Child-Pugh s score and ICG retention rates (percentage of total injected ICG dose) at 15 min in the cirrhotic patients. Note that there is dots overlap as some patients had same ICG R15 rate. Thus, 53 dots represent all 75 cirrhotic patients. A previous study showed that QSPECT separated normal from cirrhotic livers with a sensitivity of 97% [24]. In the present study, we assessed QSPECT as a quantitative test for hepatic function in cirrhotic and non-cirrhotic patients and compared it with a clinical scoring system (for cirrhotic patients) and with ICG-R15 in cirrhotic and non-cirrhotic patients. We chose the ICG-R15 as our gold-standard measure due to its being very popular clinically and because of its convenience in one time blood sampling. In addition, ICG-R15 is considered to be one of the most valuable and reliable tests for assessing hepatic functional reserve and predicting post-hepatectomy liver failure in cirrhotic patients [2,4,8,9,25 30]. Nevertheless, it should be recognized that the use of ICG retention test as a gold standard is controversial and neither ICG-R15 nor Child-Pugh scoring would be considered absolute predictors of liver function. Although the liver volumes were similar among the three groups, the patients with more advanced liver disease (i.e. Child-Pugh Class C) had a significantly smaller liver. Fig. 5. Correlation between quantitative liver uptake as measured by SPECT of the liver and ICG retention rates (percentage of total injected ICG dose) at 15 min in the cirrhotic patients. % of ID: percentage of injected dose of Tc-99m-phytate colloid. Fig. 7. Receiver operating characteristic curve for quantitative liver uptake as measured by SPECT of the liver in the cirrhotic patients. AUC, area under curve.

6 E. Zuckerman et al. / Journal of Hepatology 39 (2003) However, we included only six Child s C patients in order to test the ability of the QSPECT technique to finely discriminate between less advanced cirrhotic patients. In addition, we have not separately measured the right and left lobes that may have a different volume in the course of the cirrhotic process. Nevertheless, the QLU and %ID/ml of liver tissue were significantly decreased in the cirrhotic patients compared to the non-cirrhotics and healthy controls (P, 0:001). None of the non-cirrhotic patients with CLD had uptake less than 30% (Fig. 1). These data can be used as an additional parameter to detect cirrhosis in patients with CLD or to distinguish cirrhotics from non-cirrhotic patients when liver biopsy is not feasible. In addition, QLU higher than 45.3% could be able to distinguish between noncirrhotic patients with high and low fibrosis score with a sensitivity of 100%. Cirrhotic patients had a significantly higher rate of ICG retention than the non-cirrhotic patients: 20.9 versus 10.8% (P, 0:0001) (Fig. 3). None of the non-cirrhotic patients with CLD had ICG-R15 value greater than 21% although there was an overlap between the two groups in the low range of ICG retention rate (i.e. 6 20%). Therefore, ICG- R15 above 21% may be useful in distinguishing cirrhotics from non-cirrhotic patients with CLD. Many centers, in which a large number of hepatic resections or non-hepatic operations are being performed in cirrhotic patients each year, include the ICG-R15 test in the pre-operative evaluation of patients with CLD [2 4,25 30, 35]. A cut-off of 14% retention rate of ICG at 15 min is often used for decision-making regarding the extent of hepatic resection in cirrhotic patients with HCC [24,28,38]. In patients with ICG-R15. 20%, major resection is prohibited and in the majority, even a very limited resection is contraindicated in order to avoid post-operative liver failure [24,28,38]. The best cutoff value of QLU discriminating cirrhotic patients having ICG-R15 $ 15% and ICG-R15,15% was 33.3% with a sensitivity of 80% and a specificity of 100%. These results imply that all patients with liver uptake greater than 33.3% have ICG R15 $15%. Quantitative tests can be used to identify patients with relatively preserved hepatic function as determined by clinical parameters, who are nevertheless at high risk to develop post-operative hepatic failure. As demonstrated in Fig. 5, a highly significant inverse correlation between ICG- R15 rates and quantitative liver uptake was found (r ¼ 20:84, P, 0:0001). Although a significant correlation between the clinical score (i.e. Child-Pugh) and the quantitative tests (i.e. ICG R15 and QSPECT) was also found (Figs. 3 and 6) it was weaker than the former. Importantly, 16 of 44 cirrhotic patients with Child-Pugh class A, had ICG-R15 of $15% which puts them in high risk to develop post-hepatectomy liver failure in spite of their favorable clinical score (Fig. 6). Similarly, 12 of 44 cirrhotic patients with Child-Pugh class A had QLU of less than 33% (the best discriminating value for ICG-R15 of 15% by ROC curve analysis) (Fig. 4). Both, ICG-R15 and QSPECT may add an additional quantitative information which may have an impact on decision-making regarding surgery in these patients. The possible advantage of quantitative liver uptake as measured by SPECT over ICG-R15 and other tests is its ability to quantify the spleen volume and individual spleen uptake which reflect liver disease severity and portal hypertension in most patients. In fact, the increased quantitative spleen uptake found in the cirrhotic and non-cirrhotic liver disease was caused by a significant increase in spleen volume without change in the %ID/ml of spleen tissue. A large spleen with normal uptake per ml of splenic tissue may represent spleen hyperplasia caused by portal hypertension. The relatively weak correlation between the spleen volume and QLU (r ¼ 0:59) and %ID/ml of liver tissue (r ¼ 0:58) may indicate that QSPECT can separately detect a decreased radiocolloid concentrations in the liver due to fibrosis and increase in splenic tissue secondary to portal hypertension. in cirrhotic patients. The results of the present study indicate that quantitative liver uptake, may be a useful non-invasive and accurate quantitative test for hepatic function in cirrhotic patients. At this stage, it may provide additional information regarding liver function to the more conventional tests being used. 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