Hepatitis: Mori Y

Moriishi K, Mori Y, Matsuura Y. · Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita, Osaka 565-0871, Japan. · Uirusu. · Pubmed #19374196 links to  free full text

Abstract: Hepatitis C virus (HCV) is a major causative agent of blood-borne hepatitis. Most of the HCV-positive individuals have been chronically infected with the virus for decades, leading to development of steatosis, cirrhosis and ultimately hepatocellular carcinoma. In addition, cryoglobulinemia and type 2 diabetes mellitus are associated with a chronic infection with HCV. Hepatocellular carcinoma induced by HCV infection is not caused by only the repeated inflammations but also the biological activity of HCV proteins. HCV core protein has been reported as a component of the viral nucleocapsid as well as the pathogenic factor that could induce the production of oxidative stress and progression of cell growth. In this review, we summarize the current status of our knowledge regarding to the processing and pathogenicity of HCV core protein.

Mori Y, Moriishi K, Matsuura Y. · Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. · Int J Biochem Cell Biol. · Pubmed #18321762 No free full text.

Abstract: Hepatitis C virus (HCV) is a major cause of chronic liver diseases, including steatosis, cirrhosis and hepatocellular carcinoma, and epidemiological studies indicate that HCV is also associated with insulin resistance and type 2 diabetes mellitus. The HCV core protein is not only a viral structural component but also a pathogenic factor, since its expression leads to the development of liver steatosis, insulin resistance and hepatocellular carcinoma in mice. The nuclear proteasome activator PA28gamma/REGgamma, which specifically binds to the core protein, is required for the virulence of the core protein. Elucidation of the mechanisms by which HCV core protein participates in the above conditions may provide clues toward the development of novel therapeutic measures for chronic hepatitis C.

Uchiyama-Tanaka Y, Mori Y, Kishimoto N, Nose A, Kijima Y, Nagata T, Umeda Y, Masaki H, Matsubara H, Iwasaka T. · Renal Division, Department of Medicine II, Kansai Medical University, Moriguchi, Osaka, Japan. · Clin Nephrol. · Pubmed #14989635 No free full text.

Abstract: We describe the case of a 51-year-old man with hepatitis C virus (HCV) infection and a 3-month history of facial edema. Laboratory tests upon admission for renal biopsy showed normal renal function and normocomplementemia. Serum HCV antibody (Ab) and cryoglobulin were positive. Renal biopsy specimens showed features of membranous glomerulonephritis. The likely cause was immune complex-mediated glomerulonephritis associated with HCV infection. Reports of similar cases in the literature show the normocomplementemia and negative or slightly positive cryoglobulins observed in our case as well as seropositivity for circulating immune complexes containing HCV RNA. In our case, electron microscopic examination of the subepithelial glomerular lesions revealed massive virus-like particles within unusual multilayers of electron-dense deposits (EDDs), suggesting the existence of HCV in the glomeruli. In the addition to the unique histopathological feature the presence of La/SS-B antibody in his serum indicated an abnormal immune response associated with HCV. We advise him to undergo the therapy with new type of IFN such as pegIFN-alpha2a and/or anti-viral agent like ribavirin to achieve clinical and histopathological improvement.

Aoki K, Nakajima A, Mukasa K, Osawa E, Mori Y, Sekihara H. · Third Department of Internal Medicine, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan. · J Steroid Biochem Mol Biol. · Pubmed #12943737 No free full text.

Abstract: The levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) peak in human in their twenties, then decrease gradually with age. The physiological importance of DHEA was not clear until recent research reports showing that DHEA has beneficial effects on preventing diabetes, malignancy, inflammation, osteoporosis, and collagen disease. We summarize our results concerning diabetes, hepatitis, and colon cancer.In 1982, Coleman et al. [Diabetes 31 (1982) 830] reported that DHEA decreased hyperglycemia in diabetic db/db mice, which become insulin resistant. We measured hepatic gluconeogenic enzymes in an attempt to elucidate the mechanical mechanism of DHEA action. The activity and gene expression of hepatic gluconeogenic enzyme such as glucose-6-phosphatase (G6Pase) was increased in db/db mice despite hyperinsulinemia compared to control db/+m mice. DHEA, like troglitazone, decreased these levels in db/db mice. We also showed that DHEA improved the insulin resistance caused by aging or obesity using the glucose clamp technique in another animal model. In humans, the serum DHEA concentration was shown to be associated with hyperinsulinemia in diabetes. It also became clear that DHEA increased insulin secretion in old-aged db/db mice. DHEA increases not only insulin sensitivity due to the effects in the liver and muscle, but also insulin secretion.As an effect of DHEA on T-cell mediated hepatitis induced by concanavalin A (ConA), DHEA reduced hepatic injury by inhibiting several inflammatory mediators and apoptosis. As an effect of DHEA on carcinogenesis, DHEA would be a potential chemopreventative agent against colon cancer because it decreases the number of azoxymethane (AOM) induced aberrant crypt foci, which is a possible precursor to adenoma and cancer in a murine model.Thus, since DHEA has many beneficial effects experimentally, we should consider administration of DHEA in the future, and common mechanisms among these actions of DHEA should be elucidated in further studies.

Kukihara H, Moriishi K, Taguwa S, Tani H, Abe T, Mori Y, Suzuki T, Fukuhara T, Taketomi A, Maehara Y, Matsuura Y. · Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Japan. · J Virol. · Pubmed #19515777 No free full text.

Abstract: Human vesicle-associated membrane protein-associated protein (VAP) subtype A (VAP-A) and subtype B (VAP-B) are involved in the regulation of membrane trafficking, lipid transport and metabolism, and the unfolded protein response. VAP-A and VAP-B consist of the major sperm protein (MSP) domain, the coiled-coil motif, and the C-terminal transmembrane anchor and form homo- and heterodimers through the transmembrane domain. VAP-A and VAP-B interact with NS5B and NS5A of hepatitis C virus (HCV) through the MSP domain and the coiled-coil motif, respectively, and participate in the replication of HCV. VAP-C is a splicing variant of VAP-B consisting of the N-terminal half of the MSP domain of VAP-B followed by the subtype-specific frameshift sequences, and its biological function has not been well characterized. In this study, we have examined the biological functions of VAP-C in the propagation of HCV. VAP-C interacted with NS5B but not with VAP-A, VAP-B, or NS5A in immunoprecipitation analyses, and the expression of VAP-C inhibited the interaction of NS5B with VAP-A or VAP-B. Overexpression of VAP-C impaired the RNA replication of the HCV replicon and the propagation of the HCV JFH1 strain, whereas overexpression of VAP-A and VAP-B enhanced the replication. Furthermore, the expression of VAP-C was observed in various tissues, whereas it was barely detected in the liver. These results suggest that VAP-C acts as a negative regulator of HCV propagation and that the expression of VAP-C may participate in the determination of tissue tropism of HCV propagation.

Okamoto K, Mori Y, Komoda Y, Okamoto T, Okochi M, Takeda M, Suzuki T, Moriishi K, Matsuura Y. · Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. · J Virol. · Pubmed #18562515 links to  free full text

Abstract: Hepatitis C virus (HCV) core protein has shown to be localized in the detergent-resistant membrane (DRM), which is distinct from the classical raft fraction including caveolin, although the biological significance of the DRM localization of the core protein has not been determined. The HCV core protein is cleaved off from a precursor polyprotein at the lumen side of Ala(191) by signal peptidase and is then further processed by signal peptide peptidase (SPP) within the transmembrane region. In this study, we examined the role of SPP in the localization of the HCV core protein in the DRM and in viral propagation. The C terminus of the HCV core protein cleaved by SPP in 293T cells was identified as Phe(177) by mass spectrometry. Mutations introduced into two residues (Ile(176) and Phe(177)) upstream of the cleavage site of the core protein abrogated processing by SPP and localization in the DRM fraction. Expression of a dominant-negative SPP or treatment with an SPP inhibitor, L685,458, resulted in reductions in the levels of processed core protein localized in the DRM fraction. The production of HCV RNA in cells persistently infected with strain JFH-1 was impaired by treatment with the SPP inhibitor. Furthermore, mutant JFH-1 viruses bearing SPP-resistant mutations in the core protein failed to propagate in a permissive cell line. These results suggest that intramembrane processing of HCV core protein by SPP is required for the localization of the HCV core protein in the DRM and for viral propagation.

Yamashita T, Unno H, Mori Y, Tani H, Moriishi K, Takamizawa A, Agoh M, Tsukihara T, Matsuura Y. · Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. · Virology. · Pubmed #18201743 No free full text.

Abstract: The NS3 protein of Japanese encephalitis virus (JEV) is a large multifunctional protein possessing protease, helicase, and nucleoside 5'-triphosphatase (NTPase) activities, and plays important roles in the processing of a viral polyprotein and replication. To clarify the enzymatic properties of NS3 protein from a structural point of view, an enzymatically active fragment of the JEV NTPase/helicase catalytic domain was expressed in bacteria and the crystal structure was determined at 1.8 A resolution. JEV helicase is composed of three domains, displays an asymmetric distribution of charges on its surface, and contains a tunnel large enough to accommodate single-stranded RNA. Each of the motifs I (Walker A motif), II (Walker B motif) and VI was composed of an NTP-binding pocket. Mutation analyses revealed that all of the residues in the Walker A motif (Gly(199), Lys(200) and Thr(201)), in addition to the polar residues within the NTP-binding pocket (Gln(457), Arg(461) and Arg(464)), and also Arg(458) in the outside of the pocket in the motif IV were crucial for ATPase and helicase activities and virus replication. Lys(200) was particularly indispensable, and could not be exchanged for other amino acid residues without sacrificing these activities. The structure of the NTP-binding pocket of JEV is well conserved in dengue virus and yellow fever virus, while different from that of hepatitis C virus. The detailed structural comparison among the viruses of the family Flaviviridae should help in clarifying the molecular mechanism of viral replication and in providing rationale for the development of appropriate therapeutics.

Taguwa S, Okamoto T, Abe T, Mori Y, Suzuki T, Moriishi K, Matsuura Y. · Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. · J Virol. · Pubmed #18160438 links to  free full text

Abstract: Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is required for the replication of the viral genome and is involved in several host signaling pathways. To gain further insight into the functional role of NS5A in HCV replication, we screened human cDNA libraries by a yeast two-hybrid system using NS5A as the bait and identified human butyrate-induced transcript 1 (hB-ind1) as a novel NS5A-binding protein. Endogenously and exogenously expressed hB-ind1 was coimmunoprecipitated with NS5A of various genotypes through the coiled-coil domain of hB-ind1. The small interfering RNA (siRNA)-mediated knockdown of hB-ind1 in human hepatoma cell lines suppressed the replication of HCV RNA replicons and the production of infectious particles of HCV genotype 2a strain JFH1. Furthermore, these reductions were canceled by the expression of an siRNA-resistant hB-ind1 mutant. Among the NS5A-binding host proteins involved in HCV replication, hB-ind1 exhibited binding with FKBP8, and hB-ind1 interacted with Hsp90 through the FxxW motif in its N-terminal p23 homology domain. The impairment of the replication of HCV RNA replicons and of the production of infectious particles of JFH1 virus in the hB-ind1 knockdown cell lines was not reversed by the expression of an siRNA-resistant hB-ind1 mutant in which the FxxW motif was replaced by AxxA. These results suggest that hB-ind1 plays a crucial role in HCV RNA replication and the propagation of JFH1 virus through interaction with viral and host proteins.

Takikawa Y, Yasumi Y, Sato A, Endo R, Suzuki K, Mori Y, Akasaka H, Miura Y, Sawai T, Okamoto H. · First Department of Internal Medicine, Iwate Medical University, Morioka, Japan. · Hepatol Res. · Pubmed #17300712 No free full text.

Abstract: A 65-year-old Japanese man was hospitalized because of acute hepatitis and severe cholestasis due to hepatitis E virus (HEV) infection combined with a drug reaction to a cold preparation. He died of disseminated intravascular coagulation and severe intestinal bleeding due to systemic cytomegalovirus reactivation following the development of severe eruptions with marked eosinophilia due to drug hypersensitivity to taurine and ursodeoxycholate preparations. The close interaction between viral infection or reactivation and drug hypersensitivity was considered as a pathophysiology in this case, which emphasizes the need for further study of the immunological mechanism of the interaction.

Moriishi K, Mochizuki R, Moriya K, Miyamoto H, Mori Y, Abe T, Murata S, Tanaka K, Miyamura T, Suzuki T, Koike K, Matsuura Y. · Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan. · Proc Natl Acad Sci U S A. · Pubmed #17234812 links to  free full text

Abstract: Hepatitis C virus (HCV) is a major cause of chronic liver disease that frequently leads to steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCV core protein is not only a component of viral particles but also a multifunctional protein because liver steatosis and HCC are developed in HCV core gene-transgenic (CoreTg) mice. Proteasome activator PA28gamma/REGgamma regulates host and viral proteins such as nuclear hormone receptors and HCV core protein. Here we show that a knockout of the PA28gamma gene induces the accumulation of HCV core protein in the nucleus of hepatocytes of CoreTg mice and disrupts development of both hepatic steatosis and HCC. Furthermore, the genes related to fatty acid biosynthesis and srebp-1c promoter activity were up-regulated by HCV core protein in the cell line and the mouse liver in a PA28gamma-dependent manner. Heterodimer composed of liver X receptor alpha (LXRalpha) and retinoid X receptor alpha (RXRalpha) is known to up-regulate srebp-1c promoter activity. Our data also show that HCV core protein enhances the binding of LXRalpha/RXRalpha to LXR-response element in the presence but not the absence of PA28gamma. These findings suggest that PA28gamma plays a crucial role in the development of liver pathology induced by HCV infection.

Honda M, Kawashima Y, Kawamura H, Fujikawa H, Kikuchi K, Ohashi H, Mori Y, Miyakawa H, Ishibashi M. · Fourth Department of Medicine, Teikyo University Shool of Medicine, Kawasaki. · Intern Med. · Pubmed #17139123 links to  free full text

Abstract: Here, we report a case of acute liver dysfunction complicated with uncontrollable glycemia due to insulin antibody. The patient was admitted to our hospital due to diabetic ketoacidosis. He was administered insulin immediately, however, his fasting plasma glucose level remained unstable despite the insulin treatment. Blood biochemistry revealed severe liver dysfunction, although no markers including hepatitis virus or autoantibodies associated with autoimmune liver diseases were detected. The 125I-insulin binding rate was high (54%). The characteristics of insulin antibody in this patient were similar to the antibodies of IAS patients, therefore we administered oral glucocorticoid against insulin antibody. The reduction in the 125I-insulin binding rate and the binding capacity of the high affinity site of insulin antibodies were balanced after oral glucocorticoid therapy. In addition, preprandial subcutaneous regular insulin was switched to lispro insulin. Postprandial plasma glucose levels were relatively improved by lispro insulin. The etiology of acute liver dysfunction was unknown, however, we believe that the combination of oral glucocorticoid and lispro insulin was suitable and useful for preventing recurrent liver dysfunction in this patient.

Nakai K, Okamoto T, Kimura-Someya T, Ishii K, Lim CK, Tani H, Matsuo E, Abe T, Mori Y, Suzuki T, Miyamura T, Nunberg JH, Moriishi K, Matsuura Y. · Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita, Osaka 565-0871, Japan. · J Virol. · Pubmed #16971440 links to  free full text

Abstract: Hepatitis C virus (HCV) contains two membrane-associated envelope glycoproteins, E1 and E2, which assemble as a heterodimer in the endoplasmic reticulum (ER). In this study, predictive algorithms and genetic analyses of deletion mutants and glycosylation site variants of the E1 glycoprotein were used to suggest that the glycoprotein can adopt two topologies in the ER membrane: the conventional type I membrane topology and a polytopic topology in which the protein spans the ER membrane twice with an intervening cytoplasmic loop (amino acid residues 288 to 360). We also demonstrate that the E1 glycoprotein is able to associate with the HCV core protein, but only upon oligomerization of the core protein in the presence of tRNA to form capsid-like structures. Yeast two-hybrid and immunoprecipitation analyses reveal that oligomerization of the core protein is promoted by amino acid residues 72 to 91 in the core. Furthermore, the association between the E1 glycoprotein and the assembled core can be recapitulated using a fusion protein containing the putative cytoplasmic loop of the E1 glycoprotein. This fusion protein is also able to compete with the intact E1 glycoprotein for binding to the core. Mutagenesis of the cytoplasmic loop of E1 was used to define a region of four amino acids (residues 312 to 315) that is important for interaction with the assembled HCV core. Taken together, our studies suggest that interaction between the self-oligomerized HCV core and the E1 glycoprotein is mediated through the cytoplasmic loop present in a polytopic form of the E1 glycoprotein.

Kurokohchi K, Arima K, Masaki T, Deguchi A, Nakai S, Morishita A, Yoneyama H, Ohgi T, Ono M, Yoshitake A, Maeta T, Mori Y, Kohi F, Nishioka M, Kuriyama S. · Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kagawa, Japan. · J Clin Immunol. · Pubmed #16779679 No free full text.

Abstract: Because the underlying mechanism of hepatocellular damages in autoimmune hepatitis (AIH) still remains unclear, analysis of CD28 and bcl-2 molecules, which are critical for T cell activation and survival, was performed in patients with AIH. The number of CD28(+)CD4(+) peripheral blood mononuclear cells (PBMC) in corticosteroid (CS)-treated patients was comparable to normal control individuals but decreased in untreated AIH patients. In contrast, the number of CD28(+)CD8(+) PBMC was decreased in both CS-treated and untreated AIH patients. Analysis of liver-infiltrating mononuclear cells (LIMC) showed that the number of CD28(+)CD4(+) and CD28(-)CD8(+) LIMC were positively correlated with the histology activity index score. Bcl-2(+)CD4(+) LIMC were observed in the portal area of the liver and the numbers fluctuated with disease activity during the time course after CS administration. By contrast, CD8(+) LIMC were shown not to express bcl-2. Taken collectively, these results suggest that bcl-2(+)CD28(+)CD4(+) and bcl-2(-)CD28(-)CD8(+) cells may play critical and distinct roles in hepatocellular damage in AIH.

Murakami K, Ishii K, Ishihara Y, Yoshizaki S, Tanaka K, Gotoh Y, Aizaki H, Kohara M, Yoshioka H, Mori Y, Manabe N, Shoji I, Sata T, Bartenschlager R, Matsuura Y, Miyamura T, Suzuki T. · Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. · Virology. · Pubmed #16678876 No free full text.

Abstract: We show that a dicistronic hepatitis C virus (HCV) genome of genotype 1b supports the production and secretion of infectious HCV particles in two independent three-dimensional (3D) culture systems, the radial-flow bioreactor and the thermoreversible gelation polymer (TGP), but not in monolayer cultures. Immunoreactive enveloped particles, which are 50-60 nm in diameter and are surrounded by membrane-like structures, are observed in the culture medium as well as at the endoplasmic reticulum membranes and in dilated cytoplasmic cisternae in spheroids of Huh-7 cells. Infection of HCV particles is neutralized by anti-E2 antibody or patient sera that interfere with E2 binding to human cells. Finally, the utility of the 3D-TGP culture system for the evaluation of antiviral drugs is shown. We conclude that the replicon-based 3D culture system allows the production of infectious HCV particles. This system is a valuable tool in studies of HCV morphogenesis in a natural host cell environment.

Hamamoto I, Nishimura Y, Okamoto T, Aizaki H, Liu M, Mori Y, Abe T, Suzuki T, Lai MM, Miyamura T, Moriishi K, Matsuura Y. · Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita, Osaka 565-0871, Japan. · J Virol. · Pubmed #16227268 links to  free full text

Abstract: The hepatitis C virus (HCV) nonstructural protein (NS) 5A is a phosphoprotein that associates with various cellular proteins and participates in the replication of the HCV genome. Human vesicle-associated membrane protein-associated protein (VAP) subtype A (VAP-A) is known to be a host factor essential for HCV replication by binding to both NS5A and NS5B. To obtain more information on the NS5A protein in HCV replication, we screened human brain and liver libraries by a yeast two-hybrid system using NS5A as bait and identified VAP-B as an NS5A-binding protein. Immunoprecipitation and mutation analyses revealed that VAP-B binds to both NS5A and NS5B in mammalian cells and forms homo- and heterodimers with VAP-A. VAP-A interacts with VAP-B through the transmembrane domain. NS5A interacts with the coiled-coil domain of VAP-B via 70 residues in the N-terminal and 341 to 344 amino acids in the C-terminal polyproline cluster region. NS5A was colocalized with VAP-B in the endoplasmic reticulum and Golgi apparatus. The specific antibody to VAP-B suppressed HCV RNA replication in a cell-free assay. Overexpression of VAP-B, but not of a mutant lacking its transmembrane domain, enhanced the expression of NS5A and NS5B and the replication of HCV RNA in Huh-7 cells harboring a subgenomic replicon. In the HCV replicon cells, the knockdown of endogenous VAP-B by small interfering RNA decreased expression of NS5B, but not of NS5A. These results suggest that VAP-B, in addition to VAP-A, plays an important role in the replication of the HCV genome.

Mori Y, Kishimoto N, Imai Y, Tanaka Y, Fujiyama A, Shibasaki Y, Nagata T, Masaki H, Umeda Y, Matsubara H, Iwasaka T. · Second Department of Internal Medicine, Kansai Medical University, Osaka. · Intern Med. · Pubmed #10888213 links to  free full text

Abstract: A 75-year-old man was admitted due to nephrotic syndrome, purpura on the legs, which was associated with hepatitis C virus (HCV), and type II mixed cryoglobulinemia. Renal biopsy revealed features of cryoglobulinemic glomerulonephritis. Since the patient was elderly and the HCV genotype was Ib, interferon-alpha for reducing HCV was not indicated. Four sessions of cryofiltration and the administration of corticosteroids improved the proteinuria and renal function strikingly without adverse effects. This case demonstrates that an elderly patient who has nephrotic syndrome caused by cryoglobulinemic glomerulonephritis associated with HCV can be treated safely by cryofiltration with low doses of oral corticosteroids.

Nakano S, Katoh T, Ohki M, Mori Y, Kageyama J, Toyama Y, Hino I, Satoh K, Ohkawa M. · Department of Radiology, Kagawa Medical University, Japan. · Radiat Med. · Pubmed #10378648 No free full text.

Abstract: PURPOSE: To evaluate pharmacologically stimulated portal flow measured by magnetic resonance (MR) imaging for assessment of liver function. MATERIALS AND METHODS: Pharmacologically stimulated portal flow was measured by phase contrast MR imaging in 27 patients when they were undergoing abdominal angiography for liver tumors or gall bladder cancer. The patients included 11 cases of liver cirrhosis and eight of chronic hepatitis. Pharmacological stimulation was done by infusion of 10 microg/Kg of nicardipine hydrochloride into the superior mesenteric artery through an angiographic catheter. We examined the correlation between stimulated or non-stimulated portal flow and biochemical liver function tests. RESULTS: Correlation coefficients and their corresponding p values between non-stimulated portal flow and the indocyanine green residual rate at 15 min after injection (ICG R15), serum albumin (ALB), total bilirubin (TB), cholinesterase (CHE), and hepaplastin test (HP) were--0.414 (0.056), 0.296 (0.134), -0.570 (0.002), 0.289 (0.153), and 0.321 (0.126), respectively, whereas those between stimulated portal flow and ICG R15, ALB, TB, CHE, and HP were--0.561 (0.007), 0.411 (0.033), -0.509 (0.007), 0.445 (0.023), and 0.494 (0.014), respectively. CONCLUSION: Stimulated portal flow showed better correlations with biochemical liver function tests than non-stimulated portal flow. It is suggested that stimulated portal flow measurement is more useful for the evaluation of liver function than non-stimulated portal flow measurement.