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Hepatic stellate cells (HSCs) are located in the space of Disse, between liver sinusoidal endothelia cells (LSECs) and hepatocytes. They have surprised and excited hepatologists for their biological characteristics. Under physiological quiescent conditions, HSCs are the major vitamin A-storing cells of the liver, playing crucial roles in the liver development, regeneration, and tissue homeostasis. Upon injury-induced activation, HSCs convert to a pro-fibrotic state, producing the excessive extracellular matrix (ECM) and promoting angiogenesis in the liver fibrogenesis. Activated HSCs significantly contribute to liver fibrosis progression and inactivated HSCs are key to liver fibrosis regression. In this review, we summarize the comprehensive understanding of HSCs features, including their roles in normal liver and liver fibrosis in hopes of advancing the development of emerging diagnosis and treatment for hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Objectives: To systematically test the reproducibility of DKI technique in normal liver and report a complete set of DKI measurement data. Materials and methods: Thirty-two healthy volunteers were examined with liver DKI twice on the GE 3.0 T MRI scanner and reviewed by three professional experts. DKI-derived parameters fractional anisotropy of kurtosis (FAk), mean diffusivity (Md), axial diffusivity (Da), radial diffusivity (Dr), mean kurtosis (Mk), axial kurtosis (Ka), and radial kurtosis (Kr) in eight segments divided by Couinaud octagonal method were collected. Inter-class correlation coefficient (ICC) was used to assess the agreement between three experts. For each expert, the reproducibility of twice scans was evaluated by Bland–Altman method. Multivariate analysis of variance was to explore the regional distribution characteristics of DKI-derived parameters, and showed with box-plot graph. Results: Using ICC analysis, except for FAk (ICC 0.312, 0.307), other DKI metric values showed high reproducibility (0.716 < ICC < 0.907) between three experts for each of two DKI measurements. With Bland–Altman method, liver segment 5 (S5) showed the best reproducibility between two DKI measurement, and the reproducibility of segment 4 (S4) was the worst. The reproducibility of the right lobe was significantly higher than the left lobe. The values of diffusion metrics (Md, Da, and Dr) and kurtosis metrics (Mk, Ka, and Kr) existed significantly difference between the right and left hepatic lobes. Conclusion: DKI has shown excellent reproducibility in liver imaging. The range of values for multiple DKI parameters, derived from the normal liver, was reported, and may provide data reference for further clinical DKI applications. Additionally, DKI technique is a non-invasive method to reflect the perfusion or structural differences between the left and right hepatic lobes from the molecular level. [ABSTRACT FROM AUTHOR]

Background: A potential correlation between sex hormones, such as androgens and estrogens, and the development and progression of hepatocellular carcinoma (HCC) has been proposed. However, its details, in particular, aromatase status in diseased human liver has remained largely unknown. Materials and methods: We immunolocalized aromatase, 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1 and 17β-HSD type 2 in a total of 155 cases, consisting of normal liver (n = 10), nonalcoholic steatohepatitis (NASH) (n = 18), primary sclerosing cholangitis (PSC) (n = 6), primary biliary cholangitis (PBC) (n = 13), biliary atresia (n = 18), alcoholic hepatitis (n = 11), hepatitis C virus (HCV) (n = 31), HCV sustained virologic response (HCV-SVR) (n = 10), hepatitis B virus (HBV) (n = 20), HBV sustained virologic response (HBV-SVR) (n = 8) and infants (n = 10). Results: Immunoreactivity scores of aromatase in HBV (59.5 ± 30.9), HBV-SVR (68.1 ± 33.5) and infants (100.5 ± 36.6) were significantly higher than those in normal liver (26.0 ± 17.1). Scores of 17β-HSD type 1 in any etiology other than HBV (116.3 ± 23.7) and infants (120.0 ± 28.5) were significantly lower than those in normal liver (122.5 ± 8.6). Scores of 17β-HSD type 2 in NASH (74.4 ± 36.6) were significantly lower than those in normal liver (128.0 ± 29.7). Conclusion: High immunoreactivity scores of aromatase and 17β-HSD type 1 in the patients with HBV suggest a correlation between HBV infection and in situ estrogen synthesis in hepatocytes. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to determine the elastic modulus values of normal liver tissue in school-age children by shear wave elastography (SWE) and to study the factors that influence these stiffness measurements.Methods: Six hundred and four school-age children (295 girls and 309 boys) who were recruited at a hospital and had normal results of specific laboratory tests and imaging studies underwent SWE examinations. The elastic modulus values were obtained in segment V and VI for each subject and comparisons were made between age groups.Results: The mean elastic modulus values for school-age children were 6.3 ± 1.1 kPa for segment V and 6.2 ± 1.1 kPa for segment VI. A positive linear trend in liver stiffness was found for the 6 to 9-year-old age group in segments V and VI (R2 = 0.076 vs R2 = 0.085, respectively, P < .05). No statistically significant difference in liver stiffness was found between genders and between segment groups (P > .05).Conclusion: SWE is a feasible method to measure liver stiffness in the school-age population. We established a normal range of liver elastic modulus values in school-age children, which will provide a basis for evaluating the changes in liver stiffness caused by various diseases. [ABSTRACT FROM AUTHOR]

The liver is the largest glandular organ in the body and has a unique distribution of cells and biomolecules. However, the treatment outcome of end-stage liver disease is extremely poor. Single-cell sequencing is a new advanced and powerful technique for identifying rare cell populations and biomolecules by analyzing the characteristics of gene expression between individual cells. These cells and biomolecules might be used as potential targets for immunotherapy of liver diseases and contribute to the development of precise individualized treatment. Compared to whole-tissue RNA sequencing, single-cell RNA sequencing (scRNA-seq) or other single-cell histological techniques have solved the problem of cell population heterogeneity and characterize molecular changes associated with liver diseases with higher accuracy and resolution. In this review, we comprehensively summarized single-cell approaches including transcriptomic, spatial transcriptomic, immunomic, proteomic, epigenomic, and multiomic technologies, and described their application in liver physiology and pathology. We also discussed advanced techniques and recent studies in the field of single-cell; our review might provide new insights into the pathophysiological mechanisms of the liver to achieve precise and individualized treatment of liver diseases., Competing Interests: The authors have no conflict of interests related to this publication., (© 2024 Authors.)

Purpose: Hepatocellular carcinoma (HCC) on normal liver is very rare. The goal of this study was to determine the clinical manifestations and the role of ultrasonography (US) in the diagnosis of HCC arising in normal liver.Methods: The clinical data and US findings in 12 cases of surgically resected HCC in normal liver were retrospectively analyzed.Results: The patients were asymptomatic, had no hepatocarcinogenic factor, and hepatic function tests were almost normal in most cases. HCCs were large, encapsulated, and solitary, and there were predominantly well-differentiated or moderately differentiated in most cases. US showed a hypoechoic rim and lateral shadowing, suggestive of peritumoral capsule formation, and on contrast-enhanced US (CEUS), the tumor was hyperenhanced in arterial phase and washed out in postvascular phase, revealing typical HCC findings.Conclusions: US raises suspicion of HCC by showing lateral shadowing on grayscale ultrasound and hypervascularity on CEUS of the lesion. [ABSTRACT FROM AUTHOR]

Aim Past hepatitis B virus (HBV) infection is considered a risk factor for hepatocarcinogenesis, but the clinicopathological characteristics of non-B non-C hepatocellular carcinoma (NBNC-HCC) excluding past HBV infection have not been investigated. This study aimed to clarify the clinicopathological features of strictly defined NBNC-HCC. Methods Among HCC patients who underwent surgical resection at our affiliated hospitals in Nagano prefecture, Japan, between 1996 and 2012, 77 were negative for serum anti-HBV core/surface antibodies in addition to HBV surface antigen and anti-hepatitis C virus antibody without signs of autoimmune liver disease, Wilson disease, or hemochromatosis. These patients were divided into the alcohol intake-positive group (ethanol intake >20 g/day, n = 31), non-alcoholic fatty liver group (steatosis >5% and ethanol intake <20 g/day, n = 30), and cryptogenic group (no ethanol intake or steatosis, n = 16). Preoperative clinical parameters, tumor and background liver pathology, and prognosis were analyzed. Results Advanced fibrosis and steatosis were detected in 64% and 60% of all patients, respectively. Approximately 85% of the alcohol intake-positive patients had advanced fibrosis. Non-alcoholic fatty liver HCC subjects had the highest body mass index and prevalence of diabetes, but 30-40% had none to mild fibrosis. The cryptogenic group of HCC patients had the lowest incidence of accompanying hepatic inflammation/fibrosis but the largest tumor size. Recurrence/survival rates were comparable among the groups. Conclusions Liver fibrosis and steatosis are risk factors of HCC regardless of past HBV infection and ethanol consumption. The present results also indicate the possibility of hepatocarcinogenesis independent of hepatic steatosis, inflammation and fibrosis, ethanol intake, and past HBV infection. [ABSTRACT FROM AUTHOR]

Background: Several studies have investigated miRNA and mRNA co-expression to identify regulatory networks at the transcriptional level. A typical finding of these studies is the presence of both negative and positive miRNA-mRNA correlations. Negative correlations are consistent with the expected, faster degradation of target mRNAs, whereas positive correlations denote the existence of feed-forward regulations mediated by transcription factors. Both mechanisms have been characterized at the molecular level, although comprehensive methods to represent miRNA-mRNA correlations are lacking. At present, genome-wide studies are able to assess the expression of more than 1000 mature miRNAs andmore than 35,000 well-characterized human genes. Even if studies are generally restricted to a small subset of genes differentially expressed in specific diseases or experimental conditions, the number of potential correlations remains very high, and needs robust multivariate methods to be conveniently summarized by a small set of data. Results: Nonparametric Kendall correlations were calculated between miRNAs and mRNAs differentially expressed in livers of patients with acute liver failure (ALF) using normal livers as controls. Spurious correlations due to the histopathological composition of samples were removed by partial correlations. Correlations were then transformed into distances and processed by multidimensional scaling (MDS) to map the miRNA and mRNA relationships. These showed: (a) a prominent displacement of miRNA and mRNA clusters in ALF livers, as compared to control livers, indicative of gene expression dysregulation; (b) a clustering of mRNAs consistent with their functional annotations [CYP450, transcription factors, complement, proliferation, HLA class II, monocytes/macrophages, T cells, T-NK cells and B cells], as well as a clustering of miRNAs with the same seed sequence; and (c) a tendency of miRNAs and mRNAs to populate distinct regions of the MDS plot. MDS also allowed to visualize the network of miRNA-mRNA target pairs. Conclusions: Different features of miRNA and mRNA relationships can be represented as thematic maps within the framework of MDS obtained from pairwise correlations. The symmetric distribution of positive and negative correlations between miRNA and mRNA expression suggests that miRNAs are involved in a complex bidirectional molecular network, including, but not limited to, the inhibitory regulation of miRNA targets. [ABSTRACT FROM AUTHOR]

Background & Aims: There is no data to suggest that the size of bile ducts, portal venules, and hepatic arterioles varies according to age in the normal human liver. We sought to examine whether hepatic arteriolar size, wall thickness, and luminal diameter change with increasing age. Methods: Histologically normal liver specimens from 90 live and deceased donors were separated into three groups of thirty: donor age<30, 31–60, and>60years old. Trichrome-stained slides were de-identified and assessed by a liver pathologist blinded to donor age. Morphometric measurements were taken of the hepatic arteriole, the cross-sectional diameter, and its wall thickness. The arteriole was measured at its widest diameter, the arteriolar wall at its thickest portion, and the luminal diameter between its widest points. Results: There was no difference in number of arterioles or bile ducts or in arteriolar cross-sectional diameter among the groups and no correlation with age was found. An increasing arteriolar wall thickness and a decrease in luminal diameter with advancing age were noted; no difference in bile duct size among the groups was found. There was a significant difference in wall thickness/total cross-sectional diameter with extremes in age (21–30 age group vs. 71–80 age group, p =0.0009) with an accompanying significant decrease in luminal diameter/cross-sectional diameter between the same groups (p =0.00002). Conclusions: Increasing hepatic arteriolar wall thickness and decreased arteriolar cross-sectional diameter occur with increasing age in the normal human liver. [ABSTRACT FROM AUTHOR]

Summary: Background/aims: Cytokeratin-positive primitive hepatocytes or hepatic progenitor cells have been described in the fetal ductal plate, as well as in the adult canals of Hering. We examined the fate of ductal plate cells in the hilar region of the liver. Methods: Using liver sections from 10 fetuses and 15 elderly cadavers, we performed immunohistochemistry for cytokeratins 14 and 19, smooth muscle actin, vimentin and CD34. Results: At 18 weeks of gestation, cytokeratin-positive cells were evident in the ductal plate and liver parenchyma, which were separated by a narrow space. At 25 weeks, most of these positive cells had disappeared, but the remnant cells were aligned along the parenchymal margins facing the hilar portal pedicle in addition to the canals of Hering in the peripheral portal pedicle. The gallbladder bed did not contain cytokeratin 19-positive cells. Notably, even livers in the elderly contained such marginal positive cells in the hilar region. These cells were negative for smooth muscle actin and CD34, but tended to be positive for vimentin. Conclusions: Cytokeratin-positive hepatic progenitor cells are likely to exist along the hilar portal pedicle even in adults. These hilar marginal hepatocytes seem to be derived not from the fetal ductal plate, but from the liver parenchyma. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (7): 575–584 Background/aims Conflicting observations exist concerning the role of nuclear factor kappa B (NFκB) in alcoholic liver disease (ALD) in animal models. To date no studies have examined this aspect in human liver tissue. We here assessed cytokines and toll-like receptors (TLRs) expressions in conjunction with NFκB activation in non-active end-stage human ALD compared with normal livers and hepatitis C virus (HCV) related end-stage disease. Methods mRNA and protein expression were examined by quantitative PCR and Western blotting, DNA-binding by electrophoretic mobility shift assays and NFκB sub-cellular localization by immunofluorescent staining of livers. Results NFκB mRNA and protein expression as well as strong DNA-binding were preserved in ALD but significantly down-regulated in HCV compared with normal livers. P50 immunofluorescence was found in hepatocytes and bile ducts in ALD and normal livers, whereas a shift was observed in p65 staining from non-parenchymal cells in normal livers to hepatocytes in ALD. NFκB responsive genes mRNA levels IkBα and interleukin 6 were significantly higher in ALD compared with HCV. Tumour necrosis factor alpha (TNFα), TLRs 3 and 7 mRNA were up-regulated in ALD and HCV compared with normal liver with TNFα and TLR7 being the highest in HCV. Strong induction of interferon beta was found in HCV but not in ALD or normal liver tissue. Conclusions Persistent NFκB activation together with high pro-inflammatory cytokine expression and upregulation of TLR3 and TLR7 is associated with end-stage ALD in humans and could contribute to disease progression even in absence of alcohol intake. [ABSTRACT FROM AUTHOR]

Background: In addition to the biochemical components secreted in bile, aquaporin (AQP) water channels exist in hepatocyte membranes to form conduits for water movement between the sinusoid and the bile canaliculus. The aim of the current study was to analyse AQP 9 expression and localization in human hepatocellular carcinoma (HCC) and non-tumourigenic liver (NTL) tissue from patients undergoing hepatic resection. Methods: Archived tissue from 17 patients was sectioned and analysis performed using an antibody raised against AQP 9. Slides were blind-scored to determine AQP 9 distribution within HCC and NTL tissue. Results: Aquaporin 9 was predominantly expressed in the membranes of hepatocytes and demonstrated zonal distribution relative to hepatic sinusoid structure in normal liver. In HCC arising in the absence of cirrhosis AQP 9 remained membrane-localized with zonal distribution in the majority of NTL. By contrast, AQP 9 expression was significantly decreased in the HCC mass vs. pair-matched NTL. In HCC in the presence of cirrhosis, NTL was characterized by extensive AQP 9 staining in the membrane in the absence of zonal distribution and AQP 9 staining in NTL was significantly greater than that observed in the tumour mass. Conclusions: These data demonstrate that human HCC is characterized by altered AQP 9 expression and AQP 9 localization in the NTL mass is dependent on underlying liver pathology. Given the central role of AQPs in normal liver function and the potential role of AQPs during transformation and progression, these data may prove valuable in future diagnostic and/or therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract: There is indirect multiple evidence that hints at a potential role of sex steroids in development and progression of human hepatocellular carcinoma (HCC). In the present study, we have investigated androgen metabolism in a panel of human liver cancer cell lines (HA22T, Huh7, HepG2) and in normal, cirrhotic and malignant human liver tissues aiming to dissect the potential impact of individual enzyme activities and their products in normal and diseased human liver, both in vivo and in vitro. Using our intact cell analysis we were able to assess rates and pathways of androgen metabolism in living conditions. Overall, incubation of cultured cells or tissue minces with either testosterone (T) or androstenedione (Ad) used as precursor resulted in a large extent of 17βoxidation of T to Ad (cells: 28–77%; tissues: 35–50%). In malignant liver cell lines, both HA22T and Huh7 cells showed consistent amounts of the 5α-reductase enzyme products (18% and 15%, respectively), while 5β-reductase activity was more pronounced in Huh7 cells (18%) than in HA22T cells (1.8%). Interestingly, a significant extent of estrogen formation could be observed in Huh7 cells (5.4–11.5%), while no aromatase activity could be detected in HA22T cells. In HepG2 cells, along with a relatively high proportion of Ad, estrogens represented the most prominent (50–55%) end product of androgen metabolism, regardless of the precursor used. In liver tissues, equivalent results could be obtained, with a consistent proportion of 17βoxidation of T to Ad (35–50%) being observed in the majority of samples. However, while normal liver tissue samples exhibited a minor proportion of bioactive androgens (3.4%) with no aromatase products, HCC tissues showed a significant extent of aromatase activity (nearly 20%) with estrogen representing the most prominent metabolic product after 24h incubation with either T or Ad. HCV and alcoholic cirrhotic tissues displayed different patterns of androgen metabolism. The former produced limited amounts of bioactive androgens (5.3%) and considerable levels of the intermediate aromatase product 19OH-Ad (up to 28%), the latter exhibited a prevalence of androgen degradation through the 5β-reductase pathway (9.8%) and a significant extent of aromatase activity (16% as a whole). In conclusion, three major metabolic states could be depicted, depending on prevalent pathways of androgen metabolism and steroid receptor status: estrogenic, androgenic, and mixed. This model supports the idea that local estrogen biosynthesis may be implicated in human HCC and provides a basis for the exploitation of aromatase inhibitors and/or ER antagonists or selective estrogen receptor modulators (SERMs) as a new therapeutic strategy in HCC patients. [Copyright &y& Elsevier]

Background/Aims: While many data are available concerning occult hepatitis B virus (HBV) infection in patients with hepatic disorders, there is little information about this cryptic infection in individuals without liver disease. The aim of this study was to investigate the prevalence of occult HBV in the general population by examining liver specimens from a large series of HBV-surface-antigen negative individuals with no clinical and biochemical evidence of liver disease. Methods: The presence of HBV DNA was evaluated by testing, through polymerase chain reaction techniques, DNA extracts from 98 liver-disease-free individuals who underwent liver resection or needle biopsy during abdominal surgery. Sixteen of them were anti-HBV-core antigen (anti-HBc) positive and 82 were HBV serum-marker negative. All patients were negative for antibody to hepatitis C virus. Results: Occult HBV infection was revealed in 16 of the 98 cases (16.3%). In particular, 10/16 anti-HBc positive (62.5%) versus 6/82 (7.3%) HBV-seronegative individuals were occult carriers (p <0.0001). Conclusions: This study revealed that about 1/6 of the Italian general population might be carriers of occult HBV infection, and this condition is significantly associated with the anti-HBc positive status. [Copyright &y& Elsevier]

Abstract: The hepatic immunological environment, dominated by NK and NKR+ T cells, seems specialised to respond to malignant challenge. Ineffective immune responses to malignancy are likely determined by factors including alterations in the local cytokine profile. This study examines the cytokine milieu of normal and tumour-bearing liver, quantifying pro-/anti-inflammatory cytokines using modified ELISAs and real-time quantitative PCR. Cytokine protein was localised using immunohistochemistry. We demonstrate an active cytokine environment in normal liver, with high levels of inflammatory and regulatory cytokines. Inflammatory IFN-γ was increased in tumour-bearing liver (p <0.0001). However, a much greater increase in anti-inflammatory IL-10, produced by non-parenchymal cells (p <0.0005), resulted in a reduced IFN-γ:IL-10 ratio in tumour-bearing liver (p <0.02). In contrast, immunosuppressive TGF-β and IL-13 were significantly downregulated (p <0.02). Furthermore, IL-2 was not increased and IL-15 was reduced (p <0.02). The IFN-γ inducing cytokine, IL-18 was increased in tumour-bearing liver (p <0.02), while pro-inflammatory TNF-α was suppressed (p <0.05). These results suggest that, whilst there is a significant inflammatory immune response in tumour-bearing liver, evidenced by increased levels of IFN-γ, disproportionate increase in IL-10 may be a key factor in facilitating tumour progression. Therapies aimed at antagonising IL-10-mediated immunosuppression may prove a useful strategy in the future treatment of metastatic disease. [Copyright &y& Elsevier]

Abstract: In the present study, we found collagenolytic and gelatinolytic activity in the supernatants of hepatocyte cultures from rats with experimental CCl4-induced liver cirrhosis, in levels significantly higher than in comparable supernatants of hepatocyte cultures from normal rats. In addition, we clearly detected the messenger ribonucleic acids (mRNA) of four matrix metalloproteinases (MMP-2, MMP-3, MMP-10, and MMP-13) and of two tissue inhibitors of matrix metalloproteinases (TIMP-1 and TIMP-2) in hepatocytes from both normal and cirrhotic rats by RT-PCR and by in situ hybridization. Finally, we demonstrated MMP-2, MMP-3, and MMP-13 and TIMP-1 and TIMP-2 proteins in the same hepatocyte preparations by immunostaining. We conclude that rat hepatocytes produce the major enzymes and inhibitors involved in liver ECM modulation and therefore suggests that they might participate actively in the pathophysiology of liver cirrhosis in rats. [Copyright &y& Elsevier]

It is hypothesized that the cause of myocardiopathy is oxidative damage to mitochondrial DNA. To clarify this hypothesis, DNA polymerase γ activity, which is related to the final step of mitochondrial DNA repair or renewal, was measured. One cycle of treatment consisted of five injections of adriamycin over 5 days at a dose of 1 mg/kg of body weight per day and then 2 days resting time. DNA polymerase γ activities in the heart after one cycle of treatment were lower than the control level. However, DNA polymerase γ activities increased with continued adriamycin treatment, reaching a maximum level in the heart at 14 days after two cycles of adriamycin treatment. Induction of DNA polymerase γ activity was found in rat heart following three and four cycles of administration. Under these conditions, it is doubtful that mitochondrial DNA is the direct target of adriamycin administration. The damaged mitochondrial DNA may be protected by actions of the renewal or repair systems, maintaining mitochondrial function in the heart. Rat hearts at 7 days after one cycle of adriamycin treatment show morphological changes in the mitochondria that include matrix swelling and cristae disorganization, as seen in cardiac cells by electron microscopy; however, 28 days after treatment, the mitochondria appear to have recovered. [Copyright &y& Elsevier]

The binding of prostaglandin (PG) E1 and Iloprost, a chemically stable PGI2-analogue, to purified plasma cell membranes (LPZM) from liver tissue samples obtained at surgery revealed heterogeneity of the binding sites identifying high and low affinity subpopulations. In contrast to these findings only high affinity binding sites were characterized for PGE2. Displacement studies exhibited the highest competition for the PGE1-sites by PGE1 and subsequently by PGE2, Iloprost, PGD2 and PGF2 α. The binding of PGE2 to the hepatic receptor could be best displaced by PGE2 and subsequently by PGE1 and Iloprost, PGD2 and PGF2 α. In addition, PGE1, PGE2 and Iloprost enhanced cAMP-production dose-dependently over baseline. Clinical studies revealed a remarkably lower binding capacity for PGE1 in hepatocellular cancer tissue than in noral liver parenchyma. The different binding behaviour of PGE1 (Iloprost) and PGE2 for the first time provides evidence that PGE1 and PGI2 like at platelet membranes occupate the same receptor also at human LPZM. Since a reasonable number of binding sites for these substances and an enhanced cAMP-production were shown in the liver, the study indicates a regulatory role of PGs in hepatic function. [ABSTRACT FROM AUTHOR]

ABSTRACT- Aims/Background: The anatomic structure of the liver suggests that it is a place of intense trafficking between intra-hepatic and peripheral blood compartment leukocytes. Furthermore, the liver contains a large number of passenger leukocytes that may play a role in the appearance of donor-type microchimerism after transplantation. In this study, we aimed to define the principal lymphocyte sub-populations contained in donor peripheral blood and liver grafts and in normal liver removed during minimally invasive surgery. Methods: Liver biopsies were taken at the time of vascular clampage during liver extraction from donors in a brain dead state (GI: n=14). Normal liver biopsies were removed during minimaly invasive surgery (GII: n=10). Results: We observed evidence of the presence of lymphocytic activation associated with the two major CD8+ lymphocyte and natural killer (NK) cell populations in the two groups, with a significant increase in TCR γδ-bearing lymphocyte receptors between normal liver and the liver graft. Conclusions: The presence of activated leukocytes in the graft could have a fundamental role in induction of peripheral tolerance. This activation could be the result of a basic immunological response linked to the interaction of T cells and NK cells, and of secondary activation due to stress and the conditions necessary for organ removal from donors in a brain dead state. [ABSTRACT FROM AUTHOR]

The expression of proliferating cell nuclear antigen (PCNA) was examined in normal human and rat liver fixed in either formaldehyde or methanol, and was compared with the incorporation of bromo-deoxyuridine (BrdU) in S-phase cells. Codistribution of PCNA and BrdU was assessed in rat liver by double immunohistochemical staining using PC10 and anti-BrdU monoclonal antibodies to identify labelled nuclei of parenchymal and sinusoidal cells. In formaldehyde-fixed human biopsies (n = 13) PCNA-labelling index (PCNA LI) was 0.43 ± 0.24% (mean ± SEM) for hepatocytes and 0.09 ± 0.03% for sinusoidal cells. A great inter-specimen variability was observed and a preferential lobular distribution was not evident. In methanol-fixed human liver (n = 8) the immunostaining was strong. PCNA LI was 0.05 ± 0.01%) for hepatocytes and 0.14 ± 0.01% for sinusoidal cells. 75% of labelled hepatocytes and 60% of labelled sinusoidal cells were found in acinar zone 1. In formaldehyde-fixed rat liver (n = 10) a weak nuclear staining and a great interspecimen variability were evident. LI was 0.13 ± 0.07%) for hepatocytes and 0.40 ± 0.21% for sinusoidal cells without preferential acinar distribution. In methanol-fixed rat liver (n = 10), PCNA LI was 0.14 ± 0.02% for hepatocytes and 0.40 ± 0.04% for sinusoidal cells. 64% of labelled hepatocytes and 50% of labelled sinusoidal cells were found in zone 1. Only on methanol-fixed material did double immunohistochemistry show an almost complete overlap of BrdU and PCNA labelling. The PCNA LIs and the zonal distribution of labelled nuclei as obtained in methanol-fixed material are in keeping with previous reports using 3H-thymidine (3H-Thy) incorporation, suggesting that PCNA immunostaining represents a valid alternative to 3H-Thy. In addition, the present data support the hypothesis that S-phase associated PCNA is more selectively retained in methanol-fixed liver tissue. [ABSTRACT FROM AUTHOR]

ABSTRACT- A model of pressure profile along the sinusoids in the liver is presented. The major prerequisite is a converging sinusoidal flow pattern through a network of tubes with almost equal diameter. In this case the main hemodynamic resistance is located downstream at the outlet. Different geometric configurations (sphere, cylinder, and sections of these) are considered, and it is concluded that the precise shape of the microcirculatory unit is not crucial. The applicability in cirrhosis is considered in relation to a decreased diameter and number of the sinusoids in this condition. Estimated pressure profiles along the sinusoids indicate a steep downstream pressure fall in cirrhosis, implying that the spatial average of sinusoidal pressure is close to that of the inlet, i.e. portal pressure. Another prediction is an increased blood flow rate (flow rate per vessel) in the region near the outlet of the sinusoids. [ABSTRACT FROM AUTHOR]

Focal adhesion kinase (FAK) is over-expressed and is correlated with aggressiveness in adult hepatocellular carcinoma (HCC). Inhibition of FAK decreases HCC invasiveness by down-regulating Enhancer of Zeste homolog 2 (EZH2), an epigenetic controller, that acts in transcriptional repression of a large number of genes via histone 3 methylation of lysine 27 (H3K27me3). Here, we investigated the hepatic expression of total FAK, EZH2, H3K27me3, and proliferating cell nuclear antigen (PCNA) in 17 pediatric HCCs and 8 healthy livers (CTRL). Quantitative imaging analysis showed that FAK gene/protein expression is up-regulated in HCCs compared to CTRL and, among tumor samples the levels of this gene/protein are significantly higher in cirrhotic HCCs than in a healthy milieu. Accordingly, the protein levels of EZH2 were also significantly increased in HCCs from a cirrhotic background. Intriguingly, the protein expression of FAK, EZH2, and PCNA significantly inversely correlated with tumor size. Finally, in HCC samples, mainly in cirrhotic background, the up-regulation of FAK gene positively correlated with that observed in β-Catenin gene. Conclusion: FAK gene/protein is over-expressed in pediatric HCCs concomitantly to EZH2 protein and β-Catenin gene, with a more significant up-regulation in a cirrhotic background. This triad of interactors deserves further investigations for translational application. [ABSTRACT FROM AUTHOR]

Objectives: To systematically test the reproducibility of DKI technique in normal liver and report a complete set of DKI measurement data., Materials and Methods: Thirty-two healthy volunteers were examined with liver DKI twice on the GE 3.0 T MRI scanner and reviewed by three professional experts. DKI-derived parameters fractional anisotropy of kurtosis (FAk), mean diffusivity (Md), axial diffusivity (Da), radial diffusivity (Dr), mean kurtosis (Mk), axial kurtosis (Ka), and radial kurtosis (Kr) in eight segments divided by Couinaud octagonal method were collected. Inter-class correlation coefficient (ICC) was used to assess the agreement between three experts. For each expert, the reproducibility of twice scans was evaluated by Bland-Altman method. Multivariate analysis of variance was to explore the regional distribution characteristics of DKI-derived parameters, and showed with box-plot graph., Results: Using ICC analysis, except for FAk (ICC 0.312, 0.307), other DKI metric values showed high reproducibility (0.716 < ICC < 0.907) between three experts for each of two DKI measurements. With Bland-Altman method, liver segment 5 (S5) showed the best reproducibility between two DKI measurement, and the reproducibility of segment 4 (S4) was the worst. The reproducibility of the right lobe was significantly higher than the left lobe. The values of diffusion metrics (Md, Da, and Dr) and kurtosis metrics (Mk, Ka, and Kr) existed significantly difference between the right and left hepatic lobes., Conclusion: DKI has shown excellent reproducibility in liver imaging. The range of values for multiple DKI parameters, derived from the normal liver, was reported, and may provide data reference for further clinical DKI applications. Additionally, DKI technique is a non-invasive method to reflect the perfusion or structural differences between the left and right hepatic lobes from the molecular level.

We herein report a 48-year-old healthy woman who visited our hospital to investigate a 25-mm space-occupying lesion in the liver. The tumor was irregularly shaped and exhibited heterogeneous enhancement on dynamic computed tomography (CT). Whole-body positron emission tomography-CT showed an abnormal fluorodeoxyglucose uptake in the liver tumor, with a maximum standardized uptake value of 12.82. During the ensuing three months, the tumor grew rapidly and the serum alpha-fetoprotein levels also rose; partial hepatectomy was therefore performed. Microscopic findings revealed a moderately-to-poorly differentiated hepatocellular carcinoma in the normal liver.

Glucose/fructose in beverages/foods containing high-fructose corn syrup (HFCS) are metabolized to glyceraldehyde (GA) in the liver. We previously reported that GA-derived advanced glycation end-products (toxic AGEs, TAGE) are generated and may induce the onset/progression of non-alcoholic fatty liver disease (NAFLD). We revealed that the generation of TAGE in the liver and serum TAGE levels were higher in NAFLD patients than in healthy humans. Although we propose the intracellular generation of TAGE in the normal liver, there is currently no evidence to support this, and the levels of TAGE produced have not yet been measured. In the present study, male Wister/ST rats that drank normal water or 10% HFCS 55 (HFCS beverage) were maintained for 13 weeks, and serum TAGE levels and intracellular TAGE levels in the liver were analyzed. Rats in the HFCS group drank 127.4 mL of the HFCS beverage each day. Serum TAGE levels and intracellular TAGE levels in the liver both increased in the HFCS group. A positive correlation was observed between intracellular TAGE levels in the liver and serum TAGE levels. On the other hand, in male Wister/ST rats that drank Lactobacillus beverage for 12 weeks—a commercial drink that contains glucose, fructose, and sucrose— no increases were observed in intracellular TAGE or serum TAGE levels. Intracellular TAGE were generated in the normal rat liver, and their production was promoted by HFCS, which may increase the risk of NAFLD. [ABSTRACT FROM AUTHOR]

Background A potential correlation between sex hormones, such as androgens and estrogens, and the development and progression of hepatocellular carcinoma (HCC) has been proposed. However, its details, in particular, aromatase status in diseased human liver has remained largely unknown. Materials and methods We immunolocalized aromatase, 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1 and 17β-HSD type 2 in a total of 155 cases, consisting of normal liver (n = 10), nonalcoholic steatohepatitis (NASH) (n = 18), primary sclerosing cholangitis (PSC) (n = 6), primary biliary cholangitis (PBC) (n = 13), biliary atresia (n = 18), alcoholic hepatitis (n = 11), hepatitis C virus (HCV) (n = 31), HCV sustained virologic response (HCV-SVR) (n = 10), hepatitis B virus (HBV) (n = 20), HBV sustained virologic response (HBV-SVR) (n = 8) and infants (n = 10). Results Immunoreactivity scores of aromatase in HBV (59.5 ± 30.9), HBV-SVR (68.1 ± 33.5) and infants (100.5 ± 36.6) were significantly higher than those in normal liver (26.0 ± 17.1). Scores of 17β-HSD type 1 in any etiology other than HBV (116.3 ± 23.7) and infants (120.0 ± 28.5) were significantly lower than those in normal liver (122.5 ± 8.6). Scores of 17β-HSD type 2 in NASH (74.4 ± 36.6) were significantly lower than those in normal liver (128.0 ± 29.7). Conclusion High immunoreactivity scores of aromatase and 17β-HSD type 1 in the patients with HBV suggest a correlation between HBV infection and in situ estrogen synthesis in hepatocytes.