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In the present study, using transgenic frogs that express GFP specifically in myeloid cells under the myeloperoxidase enhancer sequence, we found that myeloperoxidase-positive cells are localized in the liver cortex at the late tadpole stages. Immunohistochemical analysis revealed that myelopoiesis in the liver cortex became evident after st. 50 and reached its peak by st. 56. Transplantation experiments indicated that cells with a high density at the liver cortex were derived from the dorso-lateral plate tissue in the neurula embryo. Analysis of smear samples of the cells isolated from collagenase-treated liver tissues of the transgenic tadpoles indicated that myeloid cells were the major population of blood cells in the larval liver and that, in addition to myeloid colonies, erythroid colonies expanded in entire liver after metamorphosis. Cells that were purified from the livers of transgenic tadpoles according to the GFP expression exhibited the multi-lobed nuclei. The results of present study provide evidence that the liver cortex of the Xenopus tadpole is a major site of granulopoiesis., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study investigated the feasibility of both a reduced radiation dose and a 50% of contrast dose in multiphasic CT of the liver with a 70 kVp protocol compared with a standard-tube-voltage protocol derived from dual-energy (DE) CT (blended DE protocol) with a full-dose contrast-agents in the same patient group. This study included 46 patients who underwent multiphasic contrast-enhanced dynamic CT of the liver with both a 70 kVp and a blended DE protocols. For quantitative analysis, median CT values for the liver, aorta, and portal vein, as well as signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), were measured and calculated. In addition, as a qualitative analysis, the contrast effect and overall image quality of the abdominal organs were evaluated on a five-point scale. CNR and SNR of the hepatic parenchyma were not significantly different between the 70kV protocol and the Blended DE protocol in all phases. The 70 kVp protocol showed significantly better image quality compared with the blended DE protocol in the arterial phase ( p = 0.035) and the equilibrium layer phase ( p = 0.016). A 70 kVp CT protocol in combination with a reduced radiation dose and half-dose iodine load is feasible for multiphasic dynamic CT of the liver by maintaining the contrast enhancement effects and image quality in comparison with the blended DE CT protocol.

Purpose: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can achieve marked future liver remnant (FLR) hypertrophy but this procedure is associated with a risk of mortality due to liver failure because of an insufficient FLR functional increase, a situation comparable to small-for-size syndrome (SFSS) after living-donor liver transplantation (LDLT)., Methods: The clinical data, morphologic volume changes, and histopathologic and immunohistochemical findings in hepatocytes and bile ductules were compared between ALPPS (n = 10) and LDLT with a risk for SFSS (n = 12)., Results: Although the patient characteristics and short-term outcome differed between the groups, the mean hypertrophy ratios with respect to liver volume for the FLR after performing the first-stage ALPPS procedures resembled those in small-for-size grafts after similar time intervals: 1.702 ± 0.407 in ALPPS vs. 1.948 ± 0.252 in LDLT (P = 0.205). The histologic grades for sinusoidal dilation (P = 0.896), congestion (P = 0.922), vacuolar change (P = 0.964), hepatocanalicular cholestasis (P = 0.969), and ductular reaction (P = 0.728) within the FLR at the second-stage operation during ALPPS or implanted graft were all similar between the groups., Conclusions: The hepatic regenerative process may be similar in ALPPS and LDLT using a small-for-size graft. Reducing the hepatic vascular inflow that may be excessive for the FLR volume during the first stage of ALPPS might enhance the functional recovery since measures with a similar effect appear to lessen the likelihood of SFSS.

Purpose: To compare the occurrence of transient respiratory motion artifacts (TRMAs) in multiple arterial phases on abdominal magnetic resonance (MR) images between those obtained using gadobutrol and gadoxetate disodium., Materials and Methods: Two hundred and fourteen abdominal MR examinations (101 with gadoxetate disodium, 113 with gadobutrol) were evaluated. Dynamic three-dimensional contrast-enhanced T1-weighted imaging (CAIPIRINHA-Dixon-TWIST-VIBE) including single-breath-hold six arterial phase acquisitions was performed on a 3.0-T MRI scanner. The TRMAs frequency and the mean TRMA scores were compared between patients assessed with gadoxetate disodium and those assessed with gadobutrol. In addition, the timing of TRMAs appearing for the first time was also recorded and compared between the two groups., Results: The mean TRMA scores in all arterial phases using gadoxetate disodium were significantly worse than in those using gadobutrol (1.49 ± 0.78 vs. 1.18 ± 0.53, P < .001). Regarding the timing of the occurrence of TRMAs, the severe TRMAs frequency after the third arterial phase was significantly higher in patients using gadoxetate disodium (10/101, 10%) than in those using gadobutrol (0/113, 0%) (P < .001)., Conclusion: In multiple-arterial-phase dynamic MRI, the TRMAs frequency when using gadoxetate disodium increased compared with gadobutrol, due to intolerable respiratory suspension after the third arterial phase.

Background: Cilostazol is a type III phosphodiesterase inhibitor used to treat the symptoms of intermittent claudication. Recent studies have shown that cilostazol decreases ischemia/reperfusion (I/R) injury in several organs., Materials and Methods: We evaluated the effects of cilostazol in a rat model of liver I/R injury. Thirty male Wistar rats with liver I/R injury were divided into a cilostazol or saline (control) group (n = 15 each). Each rat was orally administered cilostazol or saline for 3 d before I/R injury. Liver I/R injury was induced via 1 h of warm ischemia of the median and left lateral liver lobes, followed by 3 h of reperfusion. The rats were then euthanized. Serum aspartate aminotransferase, alanine aminotransferase, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels were measured. The Mann-Whitney U test was used to compare the differences between the treatment groups. Histologic examination was performed on the liver tissues. We also conducted a survival study to confirm the effect of cilostazol on the mortality rate in rats. For the survival study, a liver I/R injury model with an ischemia time of 1.5 h was used, and the rats were observed for 1 wk., Results: Serum aspartate aminotransferase, alanine aminotransferase, IL-1β, and IL-6 levels were significantly lower in the cilostazol group than in the saline group. Treatment with cilostazol significantly improved pathological findings associated with liver I/R injury and increased survival rate compared to that in controls., Conclusions: Cilostazol reduced mortality and alleviated the effects of liver I/R injury in Wistar rats., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The incidence of hepatocellular carcinoma (HCC) associated with metabolic risk factors, such as diabetes and obesity, has been increasing. However, the underlying mechanism that links these diseases remains unclear., Methods: We performed genome-wide expression analysis of human liver tissues of non-viral HCC patients with or without metabolic risk factors. The upregulated genes that associated with diabetes and obesity were investigated by in vitro and in vivo experiments, and immunohistochemistry of human liver tissues was performed., Results: Among the upregulated genes, connective tissue growth factor (CTGF) expression was induced to a greater extent by combined glucose and insulin administration to human hepatoma cells. Genome-wide expression analysis revealed upregulation of a chemokine network in CTGF-overexpressing hepatoma cells, which displayed an increased ability to induce in vitro activation of macrophages, and in vivo infiltration of liver macrophages. Immunohistochemistry of human liver tissues validated the correlations between CTGF expression and diabetes or obesity as well as activation of liver macrophages in patients with non-viral HCC. Recurrence-free survival was significantly poorer in the CTGF-positive patients compared with the CTGF-negative patients (p = 0.002). Multivariate analysis determined that CTGF expression (HR 2.361; 95 % CI 1.195-4.665; p = 0.013) and vascular invasion (HR 2.367; 95 % CI 1.270-4.410; p = 0.007) were independent prognostic factors for recurrence of non-viral HCC., Conclusions: Our data suggest that CTGF could be involved in oncogenic pathways promoting non-viral HCC associated with metabolic risk factors via induction of liver inflammation and is expected to be a novel HCC risk biomarker and potential therapeutic target.

Background: We compared clinical outcomes of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) against those of classical 2-stage hepatectomy in treating metastatic liver disease., Methods: Short-term outcomes, serial changes in volume of the future liver remnant (FLR), functional FLR volume, and tumor growth activity during the treatment period, were compared between our first 11 consecutive patients treated with ALPPS and 54 patients treated with classical 2-stage hepatectomy., Results: Mortality in the ALPPS group (9%) tended to be higher than in the classical 2-stage group (2%, P = 0.341). The FLR hypertrophy ratio (FLR volume after vs. before the procedure) 1 week after the first operation in the ALPPS group (1.54 ± 0.18) exceeded that in the classical 2-stage group (1.19 ± 0.29, P = 0.005), being similar to the ratio at 3 weeks after the first procedure in the classical 2-stage group (1.40 ± 0.43). However, functional volume of the FLR in the ALPPS group 1 week after the first procedure (52.1%) tended to be smaller than that in the classical group 3 weeks after the first procedure (59.2%)., Conclusions: ALPPS should be used with extreme caution, giving special attention to postoperative complications and grade of functional liver regeneration., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

At this time, the only definitive treatment of hepatic failure is liver transplantation. However, transplantation has been limited by the severely limited supply of human donor livers. Alternatively, a regenerative medicine approach has been recently proposed in rodents that describe the production of three-dimensional whole-organ scaffolds for assembly of engineered complete organs. In the present study, we describe the decellularization of porcine livers to generate liver constructs at a scale that can be clinically relevant. Adult ischemic porcine livers were successfully decellularized using a customized perfusion protocol, the decellularization process preserved the ultrastructural extracellular matrix components, functional characteristics of the native microvascular and the bile drainage network of the liver, and growth factors necessary for angiogenesis and liver regeneration. Furthermore, isolated hepatocytes engrafted and reorganized in the porcine decellularized livers using a human-sized organ culture system. These results provide proof-of-principle for the generation of a human-sized, three-dimensional organ scaffold as a potential structure for human liver grafts reconstruction for transplantation to treat liver disease.

Background: Interleukin-18 (IL-18) is a potent proinflammatory cytokine that augments both innate and acquired immune responses. It is also a crucial regulator of lymphocyte production of interferon-γ (IFN-γ), which can promote acute cellular rejection of transplanted solid organs., Methods: To evaluate the role of IL-18 in liver transplantation, we constructed an adenoviral vector encoding IL-18 binding protein (Adex-IL18bp), which specifically suppressed the biologic activity of IL-18, and examined the effect of this suppression on liver allografts by using a high-responder rat model (ACI to Lewis) of orthotopic liver transplantation (OLTx). Donor rats were given one intravenous injection of Adex-IL18bp or Adex-LacZ (control vector) 2 d before OLTx., Results: Seven days after OLTx, overexpression of IL-18bp resulting from the adenovirus gene transfer was associated with significantly decreased serum alanine aminotransferase levels and less histologic hepatic injury in recipient rats with Adex-IL18bp-pretreated donors compared with Adex-LacZ controls. Adex-IL18bp pretreatment also significantly prolonged rat/allograft survival, inhibited expression of IFN-γ, and reduced levels (versus control values) of both CXCL10 and CX3CL1, which can be induced by IFN-γ., Conclusion: These results suggest that IL-18 has an important role in liver allograft rejection through IFN-γ and chemokines and that specific suppression of IL-18 may improve liver function early after transplantation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

High-mobility group box 1 (HMGB1) is a monocyte-derived inflammatory mediator that is released in some conditions including shock, tissue injury, and endotoxin-induced lethality. In this study, we determined the plasma and hepatic tissue levels of HMGB1 in a drug-induced rat acute liver failure (ALF) model and investigated the effect of HMGB1 blockade on ALF. Adult male Sprague-Dawley rats, weighing 250 to 300 g, were used for this study. d-galactosamine was injected into the penile vein to induce ALF. To determine HMGB1 levels, plasma and hepatic tissue samples were serially collected after the d-galactosamine injection. To test the effect of HMGB1 blockade, anti-HMGB1 polyclonal antibodies or control antibodies were injected into the penile vein right after injection of d-galactosamine. Levels of HMGB1 were increased in plasma and decreased in hepatic tissue after induction of ALF. Immunohistochemical examination for HMGB1 showed that liver from animals with ALF had little staining, whereas normal liver had strong staining in the nuclei. Injection of anti-HMGB1 antibodies resulted in significant suppression of plasma HMGB1 and hepatic enzymes, marked suppression of plasma inflammatory cytokines, marked improvement of histological findings, and significant improvement of survival. The decrease of hepatic HMGB1 was also significantly suppressed in the group injected with anti-HMGB1 antibodies. The present study suggests that in ALF, the liver may release HMGB1 into the plasma, and that neutralizing the released HMGB1 has a protective effect against injury.

Gadoxetate Sodium (Gd-EOB-DTPA) is a relatively new contrast agent used for liver examination by magnetic resonance (MR) imaging. The setting of the flip angle (FA) is very important to obtain images with high contrast in hepatocellular MR imaging. The aim of this study was to determine the optimal FA for hepatocellular MR imaging. Optimal FA was estimated using a visual evaluation by observers. We made the visual evaluation with a paired comparison test. When the overall characteristic showed a significant difference, we then evaluated the optimal FA using a yardstick analysis. The visual evaluation by observers indicated that the FA was best at 22 degrees for the overall characteristic, the contrast characteristic, and the sharpness characteristic, and for the noise characteristic, the best FA was 18 degrees. All characteristics showed a significant difference between 18 and 22 degrees. Based on our results, the most important factor was the contrast characteristic for the visual evaluation, and we concluded that the optimal FA in hepatocelluar MR imaging was 22 degrees.

In living donor liver transplantation, the safety of the donor operation is the highest priority. The introduction of the right lobe graft was late because of concerns about donor safety. We investigated donor liver regeneration by the types of resected segments as well as recipients to assess that appropriate regeneration was occurring. Eighty-seven donors were classified into 3 groups: left lateral section donors, left lobe donors, and right lobe donors. Forty-seven adult recipients were classified as either left or right lobe grafted recipients. Volumetry was retrospectively performed at 1 week, 1, 2, 3, and 6 months, and 1 year after the operation. In the right lobe donor group, the remnant liver volume was 45.4%, and it rapidly increased to 68.9% at 1 month and 89.8% at 6 months. At 6 months, the regeneration ratios were almost the same in all donor groups. The recipient liver volume increased rapidly until 2 months, exceeding the standard liver volume, and then gradually decreased to 90% of the standard liver volume. Livers of the right lobe donor group regenerated fastest in the donor groups, and the recipient liver regenerated faster than the donor liver. Analyzing liver regeneration many times with a large number of donors enabled us to understand the normal liver regeneration pattern. Although the donor livers did not reach their initial volume, the donors showed normal liver function at 1 year. The donors have returned to their normal daily activities. Donor hepatectomy, even right hepatectomy, can be safely performed with accurate preoperative volumetry and careful decision-making concerning graft-type selection.

Purpose: The aim of this study was to evaluate the frequency and magnetic resonance imaging (MRI) features of clinically benign, small (<2 cm) hyperintense hepatic lesions in the cirrhotic liver on T1-weighted MR images seen at serial MRI., Materials and Methods: This study included 189 patients with cirrhosis, who underwent hepatic MRI more than twice with an interval of at least 12 months. The initial MR images were reviewed for the presence of small hyperintense lesions on T1-weighted images. The size, location and signal intensity on T2-weighted images as well as enhancement patterns of the corresponding lesions were recorded., Results: On the initial T1-weighted MR images, 43 small hyperintense hepatic lesions were detected in 23 (12%) of 189 patients. Twelve (28%) of 43 lesions showed early enhancement and were pathologically diagnosed as hepatocellular carcinoma (HCC) during the follow-up period. Thirty-one (72%) of 43 lesions showed no early enhancement with various signal intensity on T2-weighted images (hyperintensity=4, isointensity=20, hypointensity=7). Among these 31 lesions, 12 showed no interval change, while 11 disappeared (n=10) or decreased in size (n=1). In the remaining eight lesions, seven were diagnosed as HCC on the basis of pathologic confirmation or the interval growth., Conclusion: Small hyperintense hepatic lesions on T1-weighted magnetic resonance (MR) images without early enhancement on the arterial-phase contrast-enhanced dynamic studies in patients with cirrhosis usually showed no interval growth or disappeared during the serial MRI. These lesions with additional findings of iso- or hypointensity on the T2-weighted MR images without "washout effect" on the contrast-enhanced equilibrium-phase images may more frequently be clinically benign or hyperplastic nodules than HCCs.

Liver transplantation is the only curative treatment known to date for end-stage liver disease occurring as a result of primary sclerosing cholangitis (PSC). Here, we report a case in which living donor liver transplantation (LDLT) for PSC was cancelled because of histological abnormalities in intraoperative biopsy of the donor liver. The donor was the mother of the recipient, and her preoperative evaluation revealed no abnormalities. In the donor operation, the donor liver biopsy revealed expansion of the portal zone with lymphocytic infiltration and dense concentric fibrosis developed around a bile duct. These histological findings were identical to those of early-stage PSC; therefore, the LDLT was called off. The experience in this case suggests that preoperative liver biopsy may be useful to exclude first-degree relative donors with potential PSC prior to LDLT for PSC.

Recent reports have raised concerns over the feasibility of differentiating bone marrow cells (BMCs) into functional hepatocytes. Such augmentation is considered necessary for potential clinical use of these cells in liver diseases. The present investigation was designed to determine the kinetics of transplanted BMCs and evaluate the effects of repeated bone marrow transplantation (BMT) in rat models of CCl(4)-induced liver damage. The early kinetics of transplanted BMCs was evaluated with a charge-coupled-device (CCD) camera using BMCs obtained from green fluorescent protein (GFP) transgenic (Tg) rats and followed up with in vivo imaging system (IVIS) using BMCs obtained from firefly luciferase (luc) Tg rats. We used a portal infusion system for repeated BMT. BMCs were transplanted via a peripheral vein or the portal vein (PV) once or repeatedly using this system. The results revealed that BMCs accumulated more in the damaged liver than in the intact liver. In the experimental group receiving repeated BMT via the PV, the liver fibrosis was milder than that in the group not receiving BMT, and large clusters of albumin-producing cells were detected by albumin staining. The injected BMCs were shown to accumulate in the damaged liver. This strategy of repeated BMT has potential clinical use in enhancing the number of albumin-producing cells and suppressing liver fibrosis. This combination of beneficial effects may contribute to the benefits of cell transplantation therapy. Demonstration of the benefits of BMT in this study may be expected to have great significance for clinical trials.

Background: Liver ischemia-reperfusion injury is a serious problem during liver resection and transplantation. Nitric oxide (NO) has been suggested to have a cytoprotective effect for microcirculation, while the interaction of active oxygen species and NO produces peroxynitrite anion. The present study attempts to clarify the role of NO in liver ischemia-reperfusion injury., Methods: Wistar male rats were subjected to 30 min of hepatic ischemia followed by reperfusion. The model rats were divided into the three following groups: a control group that was not administered NO synthase inhibitors, and two experimental groups that were administered either N(omega)-nitro-L-arginine methyl ester (L-NAME) or aminoguanidine. In each group, we examined active oxygen species and nitric oxide production, and investigated liver function by measuring serum transaminase levels. In addition, we conducted histopathologic examinations and microcirculation examinations using intravital videomicroscopy., Results: In the control group, NO concentrations in the plasma increased with time after reperfusion. A decrease in NO production was detected in the groups administered NO synthase inhibitors. Elevated serum transaminase levels became more prominent after L-NAME administration, while aminoguanidine administration reduced its level. The degree of microcirculation failure was found to be more prominent in the L-NAME-administered group over both the control group and the aminoguanidine-administered group. A significantly lower survival rate was observed at 6 h after reperfusion in the L-NAME-administered group over that of the other groups., Conclusions: A reduction of the ischemia-reperfusion injury is important in inhibiting the production of high-output NO and peroxynitrite, and in maintaining NO levels necessary for maintenance of microcirculation.

Background: Brief periods of hepatic ischemia produce immediate tolerance for subsequent prolonged ischemia. Although the beneficial effect of this ischemic preconditioning is recognized, the mechanism itself remains poorly understood., Methods: Male Wistar rats were divided into two groups: a control group that was subjected to 30 min of ischemia + following reperfusion, and an ischemic preconditioning group that was subjected to 5 min of ischemia + 5 min of reperfusion + 30 min of ischemia + following reperfusion. By using this model, hepatic damage, microcirculatory disturbances, and tumor necrosis factor-alpha protein production and mRNA expression were analyzed during the course of reperfusion in both groups. For the hepatic damage evaluations, hepatic enzyme levels, histology, apoptosis analysis, and intravital microfluorography for dead cells were examined. For the microcirculatory disturbance analysis, an adhesion molecule and intravital microfluorography for endothelial-adherent leukocytes were examined., Results: In the ischemic preconditioning group, ischemia/reperfusion injuries (shown by hepatic enzymes elevation, histological degeneration, and increases in the number of apoptotic cells and microfluorographic dead cells) were markedly reduced. Moreover, microcirculatory disturbances represented by intercellular adhesion molecule-1 expression and leukocyte adhesion on the endothelium were ameliorated. Tumor necrosis factor-alpha protein production and mRNA expression were also suppressed in the ischemic preconditioning group., Conclusion: The suppression of tumor necrosis factor-alpha and the subsequent amelioration of microcirculatory disturbances were observed, suggesting that the mechanism underlying the protective effect of ischemic preconditioning in hepatic ischemia/reperfusion injuries may involve tumor necrosis factor-alpha and microcirculatory regulation., (Copyright 2002 Blackwell Publishing Asia Pty Ltd)

Ischemia/reperfusion injuries are a major problem in liver resections and transplantations. Tumor necrosis factor-alpha has been widely investigated as a key mediator in the mechanism of ischemia/reperfusion injury. Upstream signal transduction mechanisms for tumor necrosis factor-alpha have not been well documented. Therefore, we assessed c-Jun N-terminal kinase activation during warm hepatic ischemia/reperfusion injuries in a rat model. Male Wistar rats were subjected to 30 minutes of ischemia followed by reperfusion. Hepatic enzymes, histological examinations, microfluorographs, and tumor necrosis factor-alpha protein production (in the serum and liver tissue) were analyzed during the course of reperfusion. c-Jun N-terminal kinase activity was measured by a radioisotope kinase assay. Ischemia/reperfusion injuries were characterized by an elevation in hepatic enzyme, the histological degeneration of hepatocytes, and an increase in the number of nonviable cells. Moreover, increased endothelial-adherent leukocytes and tumor necrosis factor-alpha protein production were also observed. c-Jun N-terminal kinase activity at 60 minutes after reperfusion was 12.4 times higher than the pre-ischemia level. These results suggest that c-Jun N-terminal kinase may play some role in the mechanism of ischemia/reperfusion injuries.

Vitronectin is a multifunctional glycoprotein present in the extracellular matrix and plasma. Changes in rat vitronectin were studied during liver regeneration after partial hepatectomy. Carbohydrate concentrations of vitronectin decreased to 2/3 of sham-operated rats at 24 h after partial hepatectomy. Carbohydrate composition and lectin reactivity indicated that N-glycosylation and sialylation of vitronectin changed markedly after partial hepatectomy, while amino acid composition did not change significantly. We previously showed that deN-glycosylation of vitronectin in vitro affects collagen binding among various ligands (Yoneda et al., Biochemistry (1998) 37, 6351-6360). Vitronectins from partially hepatectomized rats at 24 h were found to exhibit markedly enhanced binding to type I collagen. The effect of sialylation on collagen binding was further examined using enzymatically deglycosylated vitronectin of nonoperated rats. Collagen binding increased by 1.2 times after deN-glycosylation of vitronectin, while it increased more than 2.9 times after desialylation. Various glycosyltransferases in liver are known to change after partial hepatectomy, including the attenuation of N-oligosaccharide transferase. The findings therefore suggest that the collagen binding of vitronectin is modulated by the alteration of peptide glycosylation caused by postoperative physiological changes of glycosyltransferases and that the change may contribute to tissue remodeling processes.

To predict residual liver function before hepatic resection, we devised a predictive index by combining clearance values with functional liver volume measured by liver dynamic single photon emission tomography (SPET). Forty-seven patients with liver disease underwent liver dynamic SPET with 99Tcm-Sn colloid before hepatic resection. There were no operation-related deaths. Three patients died from hepatic failure more than 1 month following the operation. Their predictive indices were 0.24, 0.33 and 0.34. When the predictive index was above 0.35, no patient had symptoms of hepatic failure or died. Our data suggest that when the predictive index is above 0.35, there is a low probability of hepatic failure after hepatectomy.

Technetium-99m-DTPA-galactosyl human serum albumin (99mTc-GSA) is a new ligand that binds specifically to asialoglycoprotein receptors in hepatocytes. We performed liver dynamic SPECT using 99mTc-GSA and 99mTc-Sn colloid in nine normal control rabbits and 17 chronically CCI4-damaged rabbits (total 29 examinations), and also performed liver function tests (ICGR15, Alb, etc). Using the obtained dynamic SPECT data, we analyzed the liver kinetics of 99mTc-Sn colloid using a one-compartment model (hepatic blood flow [K]) and 99mTc-GSA using a two-compartment model (hepatic blood flow and receptor binding [K1], catabolism [K2]). As the CCl4-treated period increased, K1 decreased most significantly. K1 showed the most significant statistical correlation with the results of liver function tests, ICGR15 (p < 0.0001), Alb, PT, HP, Bil and GPT. Further, only K1 showed a correlation with the hepatic fibrosis of the HAI score. From the present results, liver dynamic SPECT using 99mTc-GSA may be said to provide a novel method for the evaluation of hepatic functional reserve.

Background: Hepatocyte growth factor (HGF) (also known as scatter factor (SF)) is a heterodimeric protein that is the most potent known complete mitogen for hepatocytes in culture. HGF is a mitogen for many epithelial cells including hepatocytes, kidney tubular epithelial cells, mammary epithelial cells, keratinocytes, etc. The protein encoded by the proto-oncogene c-met is the high affinity receptor for HGF. HGF concentration in the plasma dramatically increases after partial hepatectomy and in fulminant hepatic failure. This study describes the pharmacokinetics of HGF in the rat., Experimental Design: Human recombinant HGF (a gift from Genentech) was radioiodinated and shown to retain biologic activity and structure. Approximately 74 ng of [125I]HGF was injected into the penile vein of male Fisher rats 5 minutes after a complete bile fistula and jugular venous catheterization were performed for blood and bile sampling. Half of the rats were subjected to 70% partial hepatectomy., Results: The percentage of injected radioactivity present in the liver of control rats was 29.5% +/- 0.5% at 15 minutes and decreased to 8.6% +/- 1.0% at 120 minutes; the kidneys had 6.2% +/- 0.2% at 15 minutes, decreasing to 1.48% +/- 0.3% at 120 minutes. All the other organs examined had less than 1% of the injected radioactivity. The remaining radioactivity was present in low affinity sites in blood, bone, muscle, and skin. In control rats, radioactivity appeared in the bile within 3 minutes, reached a peak between 40 to 50 minutes, and tapered thereafter for a total 2-hour collection of 2.3% +/- 0.5%. In the partially hepatectomized rats, the HGF blood clearance was decreased (partial hepatectomy = 0.27 +/- 0.03 ml/minute; control = 0.53 +/- 0.06 ml/minute, p < 0.006), and the terminal half-life prolonged (partial hepatectomy = 124 +/- 11 minutes; control = 83 +/- 10 minutes, p < 0.03). The initial half-life for HGF, as extrapolated from the chart, was estimated at 3.8 minutes in control rats., Conclusions: Liver is the principle organ for initial uptake of [125I]HGF; disappearance from the blood suggests multicompartment kinetics with a rapid phase and a slower phase; only a portion of the hepatic uptake appears in the bile; and partial hepatectomy decreases the blood clearance of [125I]HGF. These results are correlated with previous findings bearing on the role of HGF elevation after partial hepatectomy as a stimulus for transfer of hepatocytes from G0 to G1 early in liver regeneration after partial hepatectomy.

The concentration of L-hydroxyproline in the liver of ICR female mice increased rapidly during the 8th to 11th weeks of Schistosoma mansoni infection. Free L-proline concentration began to increase about the 7th week and reached its maximum at the 8th to 9th weeks of the infection, when the granulomatous response to the schistosome eggs in the liver was most prominent, as indicated by the increase in liver wet weight and its deoxyribonucleic acid concentration. A significant increment in the total activity of ornithine-delta-transaminase (EC 2.6.1.13) and the decrease in the specific activity of proline oxidase (EC 1.4.3.2) became detectable in the liver homogenate of infected mice on the 8th week. However, changes in these enzymatic activities were not parallel to that of the hepatic free L-proline content. Intraperitoneal administration of S. mansoni egg granulomas or 15,000g x 30 min supernatant fluid of their extracts into uninfected, normal mice significantly increased the hepatic free L-proline content without any appreciable effect on the enzymatic activities of proline oxidase and ornithine-delta-transaminase. These findings suggest that S. mansoni egg granulomas contain a factor(s) which may be responsible for the elevation of free L-proline content in the fibrotic liver caused by experimental schistosomiasis mansoni.

We reported a case of pseudoinfarct (Zahn's infarct) of the liver caused by the inflammatory pseudotumor. A dense segmental staining in the area of Zahn's infarct, which was thought to be characteristic finding, was found on the hepatic angiography. This finding was supposed to be consistent with sinusoidal hyperemia according to the pathological finding.

ICR female mice infected with cercariae of Schistosoma mansoni exhibited a significant decrease in both total and specific activities of carbamoyl-phosphate synthetase (ammonia) (EC 6.3.4.16) and ornithine carbamoyltransferase (EC 2.1.3.3), and also in the serum urea level. Intraperitoneal administration of the S. mansoni egg granulomas or 15,000g X 30 min supernatant fluid of their extract into the uninfected, normal mice also significantly decreased the total and specific activities of both enzymes without any appreciable histopathological influence on their livers. S. mansoni viable eggs caused a significant decrease in the total and specific activities of carbamoyl phosphate synthetase (ammonia) alone as well as active intraperitoneal inflammation when inoculated into the normal mice by the same route. There was no difference in the amount of food intake between the control and these experimental mice. These findings suggest that the granuloma or inflammatory cells induced by schistosome eggs produce some factor(s) which may be responsible for reduction of these enzymatic activities in experimental schistosomiasis mansoni.

A methods for liver scintigraphy for finding the effective liver volume were developed. Matrix ROI (region of interest) was set on the anterior liver scintigram with 99mTc tin colloid and 198Au colloid, respectively. The various depths of liver under matrix ROI were calculated from the count rate noting the absorption coefficient. The effective liver volume was the sum total of the areas of matrix ROI to the various depths. In order to check the accuracy of this method, the effective liver volume was calculated using the liver phantom and the patient's liver scintigraphy. The volume obtained for the liver phantom was nearly equal to the real volume. The liver volume in 19 patients using 99mTc tin colloid and 198Au colloid showed good correlation with the volume as measured by computed tomography (CT) scan (r = 0.841, r = 0.749).

At the same dynamic range (DR) a constant difference of echolevels was found between two materials with different acoustic impedance in any gain-setting by the phantom study. Our retrospective study in which we compared the difference between liver-kidney echolevels with the US-findings of fatty liver indicated that the difference over 10 in echoleveled by our equipment with 3.5 MHz phased array sector scan and 42 dB DR had a possibility of the fatty infiltration of the live. In our prospective study of 1452 abdominal US-studies we found 93 cases (6.5%) with the difference over 10 in echolevel. In all these patients the difference of liver-spleen CT-numbers and liver-kidney echolevels was compared. Although the liver CT-number is normally higher than the spleen, 75 of 93 patients showed the lower liver CT-number than that of the spleen, indicating fatty infiltration of the liver. The abnormal difference of echolevels were independent from the severity of fatty infiltration. Concerning the US-findings, "bright liver" (77.4%) and "masking sign" (66.7%) were more sensitive than "vascular blurring" (44.1%) and "deep attenuation" (44.1%). But for the severe fatty infiltration with the difference over -20 H.U. between liver-spleen CT numbers, the last two findings seemed very credible. The abnormal difference between liver-kidney echolevels was most sensitive (80.7%), especially in mild cases with 0 to -19 H.U. (53 in 75 cases), and very objective than the other US-findings.

The rate of clearance (K value) of 99mTc tin colloid in the liver differentiates normal subjects from liver cirrhosis patients; so 99mTc tin colloid is as useful as 198Au colloid as a marker of liver function. There are several reports concerning volume estimation using liver scintigraphy. Our original method was devised to measure the effective liver volume by scintigraphy. By combining the K value with effective liver volume, a predictive index was obtained in order to predict the residual liver function before hepatic resection. The index in 24 patients with liver diseases was investigated before hepatic resection. Three of them died due to hepatic failure after hepatic resection. The indices were between 0.40 and 0.45 in two of these three patients and 0.338 in one. Among the patients without hepatic failure, the indices showed more than 0.45 in 19 patients and between 0.40 and 0.45 in two. These results indicate that the limitation of hepatic resection is between 0.40 and 0.45 of the predictive index.

Hepatic resection is essential in treating hepatocellular carcinoma. However, before an operation, it is difficult to predict the functional reserve in the remnant following massive resection. We devised an original method by which effective liver volume was measured by liver scintigraphy. In order to predict the residual liver function before hepatic resection in a preoperative radiocolloid study, we obtained a predictive index by combining the K values with effective liver volumes which seemed to have the estimated residual liver function. Twenty-one patients with liver or biliary tract disease were selected at random for the present study. We divided them into 3 groups in accordance with prognosis after hepatic resection. There were statistically significant difference between the deceased group who died from hepatic failure and the group who died from causes other than hepatic failure; and between the deceased group who died from hepatic failure and the living group in the preictive index (p less than 0.01). Our data suggest that if the predictive index is above 0.45, the probability of hepatic failure after hepatic resection is low. We concluded that our predictive index is useful to use in preoperative prediction of post-hepatectomic residual liver function.

Radionuclide angiography was performed by bolus injection of 99mTc-phytate in 10 patients with liver neoplasms before and after the transcatheter hepatic arterial embolization therapy. The ratio of the slopes of the upstrokes for the hepatic arterial and abdominal aortic first transit curves constitutes the regional hepatic arterial to aortic blood flow ratio (RHA/A ratio), which represents quantitatively the arterial blood flow of hepatic region of interest as a fraction of aortic blood flow. The degree of embolic dearterialization was estimated by the change of this ratio derives from the same region of interest for each patient before and after the embolization. The values and post-embolic reduction of the ratio correlated well individually with the angiographic features and other patients' data. The arterial blood supply to the tumor could not be reducted using Lipiodol alone as the embolic material in only 1 case. The finding that the splenic arterial to aortic blood flow ratio (S/A ratio), calculated in the same way, was practically unchanged after the hepatic arterial embolization indicates the good reproducibility of these measurements. This noninvasive method may be helpful to evaluate the therapeutic effect of hepatic arterial embolization.

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