Human Chronic Liver Disease Research Articles

Keratin 8 Variants are Associated with Cryptogenic Hepatitis

Hepatitis is defined as cryptogenic only after exclusion of all known etiologies. Cryptogenic hepatitis has a worldwide prevalence of 5–15% in patients with chronic liver disease and is a frequent indication for liver transplantation. Keratin 8 (K8) and 18 (K18) are the cytoskeletal intermediate filament proteins of adult hepatocytes, and murine models indicate that mutations in the encoding genes predispose to liver disease. Moreover, numerous studies showed an association of K8/K18 variants with human acute and chronic liver disease. However, there is only little known about a putative association of K8/K18 variants with cryptogenic hepatitis/cirrhosis. Therefore, we analyzed whether K8 variants associate with cryptogenic hepatitis in a German cohort of 54 patients in comparison to 65 control blood bank donors. Genomic DNA isolated from liver biopsies of cryptogenic hepatitis patients or peripheral blood of healthy donors was analyzed for K8 variants in 3 of 8 exonic regions by PCR amplification and direct DNA sequencing, covering the 9 most common of 10 previously described variants (Ku et al.; Strnad et al.). Excluding published single nucleotide polymorphisms, we found amino acid altering K8 (mostly) heterozygous variants in 14 of 54 cryptogenic hepatitis patients (25.9%) and in 4 of 65 controls (6.2%). Notably, the most K8 variants were novel. In conclusion, previously described and novel K8 variants were identified in a German cohort and associate with cryptogenic hepatitis, possibly predisposing carriers to the development of liver disease.

Simultaneous Genotyping and Quantification of Hepatitis B Virus for Genotypes B and C by Real-Time PCR Assay

Hepatitis B virus (HBV) is an important cause of human chronic liver diseases and is a major public health problem. Viral load and HBV genotype play critical roles in determining clinical outcomes and response to antiviral treatment in hepatitis B patients. Viral genotype detection and quantification assays are currently in use with different levels of effectiveness. In this study, the performance of a real-time genotyping and quantitative PCR (GQ-PCR)-based assay was evaluated. Through the use of genotype-specific primers and probes, this assay provides simultaneous identification and quantification of genotypes B and C in a single reaction. Our GQ-PCR correctly identified all predefined genotypes B and C, and no cross-reaction between genotypes B and C were observed. The GQ-PCR identified more cases of HBV infections with mixed genotypes B and C than direct sequencing did. Samples from 127 HBV-infected Chinese patients were genotyped with GQ-PCR, revealing 56.7% HBV as genotype B, 13.4% as genotype C, and 29.8% as mixed genotypes B and C. This assay provides a reliable, efficient, and cost-effective means for quantification of the B and C genotypes of HBV in single or mixed infections. This assay is suitable for sequential monitoring of viral load levels and for determining the relationship between the genotype viral load and stage of disease in Asians.

Smad3-Mediated Signals Showing Similarities and Differences Between Epithelial and Mesenchymal Cells in Human Chronic Liver Diseases

Smad3-Mediated Signals Showing Similarities and Differences Between Epithelial and Mesenchymal Cells in Human Chronic Liver Diseases

Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin-positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NFkappaB) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NFkappaB subunit by RNA interference. TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NFkappaB-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration.

The Disulfide Bonds in Glycoprotein E2 of Hepatitis C Virus Reveal the Tertiary Organization of the Molecule

Hepatitis C virus (HCV), a major cause of chronic liver disease in humans, is the focus of intense research efforts worldwide. Yet structural data on the viral envelope glycoproteins E1 and E2 are scarce, in spite of their essential role in the viral life cycle. To obtain more information, we developed an efficient production system of recombinant E2 ectodomain (E2e), truncated immediately upstream its trans-membrane (TM) region, using Drosophila melanogaster cells. This system yields a majority of monomeric protein, which can be readily separated chromatographically from contaminating disulfide-linked aggregates. The isolated monomeric E2e reacts with a number of conformation-sensitive monoclonal antibodies, binds the soluble CD81 large external loop and efficiently inhibits infection of Huh7.5 cells by infectious HCV particles (HCVcc) in a dose-dependent manner, suggesting that it adopts a native conformation. These properties of E2e led us to experimentally determine the connectivity of its 9 disulfide bonds, which are strictly conserved across HCV genotypes. Furthermore, circular dichroism combined with infrared spectroscopy analyses revealed the secondary structure contents of E2e, indicating in particular about 28% β-sheet, in agreement with the consensus secondary structure predictions. The disulfide connectivity pattern, together with data on the CD81 binding site and reported E2 deletion mutants, enabled the threading of the E2e polypeptide chain onto the structural template of class II fusion proteins of related flavi- and alphaviruses. The resulting model of the tertiary organization of E2 gives key information on the antigenicity determinants of the virus, maps the receptor binding site to the interface of domains I and III, and provides insight into the nature of a putative fusogenic conformational change.

Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling

BackgroundHepatic progenitor cells (HPCs) hold a great potential for therapeutic intervention for currently untreatable liver diseases. However, in human diseases molecular mechanisms involved in proliferation and differentiation of HPCs are...

Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases

Hepatic lymphocytes are enriched in NK and NKT cells that play important roles in antiviral and antitumor defenses and in the pathogenesis of chronic liver disease. In this review, we discuss the differential distribution of NK and NKT cells in mouse, rat, and human livers, the ultrastructural similarities and differences between liver NK and NKT cells, and the regulation of liver NK and NKT cells in a variety of murine liver injury models. We also summarize recent findings about the role of NK and NKT cells in liver injury, fibrosis, and repair. In general, NK and NKT cells accelerate liver injury by producing proinflammatory cytokines and killing hepatocytes. NK cells inhibit liver fibrosis via killing early-activated and senescent-activated stellate cells and producing IFN-gamma. In regulating liver fibrosis, NKT cells appear to be less important than NK cells as a result of hepatic NKT cell tolerance. NK cells inhibit liver regeneration by producing IFN-gamma and killing hepatocytes; however, the role of NK cells on the proliferation of liver progenitor cells and the role of NKT cells in liver regeneration have been controversial. The emerging roles of NK/NKT cells in chronic human liver disease will also be discussed.Understanding the role of NK and NKT cells in the pathogenesis of chronic liver disease may help us design better therapies to treat patients with this disease.

An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease

In chronic liver disease, high circulating interleukin (IL)-6 contrasts with a poor acute phase response. We evaluated the impact of liver and circulating IL-6-receptor (IL-6R) forms on IL-6 bioactivity in chronic liver disease. IL-6, soluble IL-6-receptor and sgp130 levels were assayed in plasma from 45 patients with alcoholic liver disease, 84 with hepatitis C virus (HCV) infection undergoing transjugular liver biopsies and 15 healthy subjects. IL-6R mRNA was quantified on liver extracts from 54 patients with alcoholic liver disease with or without cirrhosis and 18 HCV-infected patients. The effect of gp130-Fc on fibrinogen secretion induced by IL-6 trans-signalling was evaluated on hepatocyte cultures. Levels of plasma IL-6 and sgp130, but not soluble IL-6R, increased with the stage of chronic liver disease, and correlated significantly with disease severity. Alcoholic liver disease patients had higher plasma IL-6 levels than hepatitis C, but lower liver IL-6R expression. In alcoholic and HCV-related liver diseases, liver IL-6R expression decreased with advanced fibrosis stage. In vitro, on hepatocytes, gp130-Fc blunted the acute phase response while soluble IL-6R enhanced IL-6 stimulation. In advanced chronic liver disease, high plasma IL-6 is associated with low liver IL-6R expression. This situation enables high plasma sgp130 to act as a major negative regulator of liver IL-6 trans-signalling, as demonstrated functionally here on hepatocytes. This might explain the poor acute phase response induced by IL-6 in chronic liver disease.

Characterization and Application of a New Monoclonal Antibody with High Specificity for Helicobacter hepaticus

Infection with Helicobacter hepaticus is suggested to play a role in the pathogenesis of chronic liver disease in humans. However, reactive antigens among Helicobacter species make the development of an H. hepaticus ELISA test with high specificity difficult. A new monoclonal antibody from a hybridoma clone (HRII-51) showed high specificity to H. hepaticus without cross-reaction to other gastrointestinal bacteria. The molecular weight of HRII-51 immunoreactive antigen was examined by Western blot of H. hepaticus probed with the monoclonal antibody HRII-51. A HRII-51-immunoreactive antigen capture ELISA was prepared in which the specific antigen was anchored by HRII-51-immobilized ELISA plate. Accuracy of HRII-51 antigen capture ELISA was examined using sera obtained from mice inoculated with Helicobacter species. Specificity of HRII-51 antigen capture ELISA was compared to that of H. hepaticus antigen-based ELISA using human sera with absorption by H. pylori cell lysate. HRII-51 immunoreactive antigen had a molecular weight of 15 kDa. Sensitivity and specificity of HRII-51 antigen capture ELISA were 87.0% and 97.6% in mice inoculated with Helicobacter species. In human sera, modification of the results by absorption with H. pylori lysate was smaller in HRII-51 antigen capture ELISA comparing with H. hepaticus-antigen-based ELISA. Use of the HRII-51 antigen capture ELISA would be a useful approach for the serodiagnosis of H. hepaticus infection in both experimental animals and humans.

Role of Caspases-9 and -4 in Glycochenodeoxycholic Acid-induced Apoptosis in HepG2 Cells

It is believed that hepatocellular damage in human chronic cholestatic liver diseases is caused by the accumulation of hydrophobic bile acids, such as glycochenodeoxycholic acid(GCDCA). Previous reports have shown that GCDCA-induced apoptosis is promoted by both mitochondria-mediated and endoplasmic reticulum(ER)stress-associated pathways in HepG2 cells and that these two pathways are linked by the action of caspase-8 on BAP31. However, the interdependence of multiple pathways remains poorly understood and the role of caspases is unclear. Thus, in the present study, we investigated the interactions among the executioner caspases in GCDCA-induced apoptotic HepG2 cells. Cells were treated for 1-24 h with GCDCA(300μM), in the presence or absence of inhibitors of caspase-9, -4 or -3(each at 30μM). Pretreatment of cells with the caspase-9 inhibitor significantly suppressed GCDCA-induced apoptosis ; however, pretreatment of cells with the caspase-4 inhibitor had no effect. Furthermore, pretreatment of cells with the caspase-9 inhibitor significantly reduced GCDCA-induced increases in caspase-3 and -4 activity, as well as the mRNA expression of BiP, a molecular chaperone located in the ER. In contrast, pretreatment of cells with the caspase-4 inhibitor had no effect. These results suggest that, in GCDCA-treated HepG2 cells, caspase-4 acts downstream of both the proapoptotic Bcl-2 protein Bax and caspase-9. Because the major mechanism underlying GCDCA-induced apoptosis involves a mitochondria-mediated pathway, it is unlikely that caspase-4 has a major role in the initiation and promotion of GCDCA-induced apoptosis.

Lymphotoxin‐β receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury†

Lymphotoxin-beta (LTbeta) is a proinflammatory cytokine and a member of the tumor necrosis factor (TNF) superfamily known for its role in mediating lymph node development and homeostasis. Our recent studies suggest a role for LTbeta in mediating the pathogenesis of human chronic liver disease. We hypothesize that LTbeta co-ordinates the wound healing response in liver injury via direct effects on hepatic stellate cells. This study used the choline-deficient, ethionine-supplemented (CDE) dietary model of chronic liver injury, which induces inflammation, liver progenitor cell proliferation, and portal fibrosis, to assess (1) the cellular expression of LTbeta, and (2) the role of LTbeta receptor (LTbetaR) in mediating wound healing, in LTbetaR(-/-) versus wild-type mice. In addition, primary isolates of hepatic stellate cells were treated with LTbetaR-ligands LTbeta and LTbeta-related inducible ligand competing for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT), and mediators of hepatic stellate cell function and fibrogenesis were assessed. LTbeta was localized to progenitor cells immediately adjacent to activated hepatic stellate cells in the periportal region of the liver in wild-type mice fed the CDE diet. LTbetaR(-/-) mice fed the CDE diet showed significantly reduced fibrosis and a dysregulated immune response. LTbetaR was demonstrated on isolated hepatic stellate cells, which when stimulated by LTbeta and LIGHT, activated the nuclear factor kappa B (NF-kappaB) signaling pathway. Neither LTbeta nor LIGHT had any effect on alpha-smooth muscle actin, tissue inhibitor of metalloproteinase 1, transforming growth factor beta, or procollagen alpha(1)(I) expression; however, leukocyte recruitment-associated factors intercellular adhesion molecule 1 and regulated upon activation T cells expressed and secreted (RANTES) were markedly up-regulated. RANTES caused the chemotaxis of a liver progenitor cell line expressing CCR5. This study suggests that LTbetaR on hepatic stellate cells may be involved in paracrine signaling with nearby LTbeta-expressing liver progenitor cells mediating recruitment of progenitor cells, hepatic stellate cells, and leukocytes required for wound healing and regeneration during chronic liver injury.

Epithelial–mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease

The relationship between bile duct damage and portal fibrosis in chronic liver diseases remains unclear. This study was designed to show whether human intrahepatic biliary epithelial cells can undergo epithelial–mesenchymal cell transition, thereby directly contributing to fibrogenesis. Primary human cholangiocytes were stimulated with transforming growth factor-β (TGFβ) or TGFβ-presenting T cells and examined for evidence of transition to a mesenchymal phenotype. Liver sections were labelled to detect antigens associated with biliary epithelial cells (cytokeratin 7 and 19 and E-cadherin), T cells (CD8), epithelial–mesenchymal transition (S100A4, vimentin and matrix metalloproteinase-2 (MMP-2)), myofibroblasts (α-smooth muscle actin) and intracellular signal-transduction mediated by phosphorylated (p)Smad 2/3; in situ hybridisation was performed to detect mRNA encoding TGFβ and S100A4. Stimulation of cultured cells with TGFβ induced the expression of pSmad2/3, S100A4 and α-smooth muscle actin; these cells became highly motile. Although normal bile ducts expressed ALK5 (TGFβ RI), low levels of TGFβ mRNA and nuclear pSmad2/3, they did not express S100A4, vimentin or MMP-2. However, TGFβ mRNA and nuclear pSmad2/3 were strongly expressed in damaged ducts, which also expressed S100A4, vimentin and MMP-2. Fibroblast-like cells which expressed S100A4 were present around many damaged bile ducts. Cells in the ‘ductular reaction' expressed both epithelial and mesenchymal markers together with high levels of TGFβ mRNA and pSmad2/3. In conclusion, the cells forming small- and medium-sized bile ducts and the ductular reaction undergo EMT during chronic liver diseases, resulting in the formation of invasive fibroblasts; this process may be driven by a response to local TGFβ, possibly presented by infiltrating T cells.

Bile acids and apoptosis modulation: an emerging role in experimental Alzheimer's disease

The potential role of apoptosis in Alzheimer's disease (AD) has been an area of intense research in recent years. Ursodeoxycholic acid (UDCA) and its taurine-conjugate, tauroursodeoxycholic acid (TUDCA) are endogenous bile acids that act as potent inhibitors of apoptosis. Their therapeutic effects have been tested in many experimental pathological conditions, including neurological disorders, such as AD. TUDCA regulates precise transcriptional and post-transcriptional events that impact mitochondrial function in neurons. TUDCA not only stabilizes the mitochondrial membrane and prevents Bax translocation, inhibiting the release of cytochrome c and the activation of caspases, but also interferes with upstream factors, including cell cycle-related proteins. In addition, TUDCA is capable of inducing survival pathways. Here, we review the role of apoptosis in AD and discuss the therapeutic potential of TUDCA in treating this disease.

Cell Type–Dependent Pro- and Anti-Inflammatory Role of Signal Transducer and Activator of Transcription 3 in Alcoholic Liver Injury

Signal transducer and activator of transcription 3 (STAT3) is known to be activated in human alcoholic liver disease, but its role in the pathogenesis of alcoholic liver injury remains obscure. The role of STAT3 in alcoholic liver injury was investigated in hepatocyte-specific STAT3 knockout (H-STAT3KO) mice and macrophage/neutrophil-specific STAT3 KO (M/N-STAT3KO) mice. Alcoholic liver injury was achieved by feeding mice a liquid diet containing 5% ethanol for up to 8 weeks. Compared with wild-type mice, feeding H-STAT3KO mice with an ethanol-containing diet induced greater hepatic steatosis, hypertriglyceridemia, and hepatic expression of lipogenic genes (sterol regulatory element-binding protein, fatty acid synthase, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase 1), but less inflammation and lower expression of hepatic proinflammatory cytokines. In contrast, ethanol-fed M/N-STAT3KO mice showed more hepatic inflammation, worse injury, and increased hepatic expression of proinflammatory cytokines compared with wild-type mice. Kupffer cells isolated from ethanol-fed H-STAT3KO mice produced similar amounts of reactive oxygen species and tumor necrosis factor alpha, whereas Kupffer cells from M/N-STAT3KO mice produced more reactive oxygen species and tumor necrosis factor alpha compared with wild-type controls. These findings suggest that STAT3 regulates hepatic inflammation in a cell type-dependent manner during alcoholic liver injury: STAT3 in hepatocytes promotes whereas STAT3 in macrophages/Kupffer cells suppresses inflammation. In addition, activation of hepatocellular STAT3 ameliorates alcoholic fatty liver via inhibition of sterol regulatory element-binding protein 1c expression.

Chronic delta hepatitis: An overview

Delta hepatitis or hepatitis D leads to acute and chronic liver disease in humans. The causative agent, the hepatitis delta virus (HDV), is a defective virus which leads to hepatitis in humans in the presence of the hepatitis B virus. This helper function of HBV is required for transmission and propagation of HDV infection but not for replication. HDV RNA replication occurs through the double-rolling circle model and does not possess a reverse transcription step. Hepatitis D-induced liver disease is immune-mediated and occurs either as co-infection of both viruses or as superinfection of a hepatitis B carrier with hepatitis D. Based on a sequence variation of 19-38%, to date seven genotypes of HDV have been described. HDV infection has declined significantly in many endemic areas in the last decades, however, due to migration to industrialized countries, this decline appears to have reached a plateau in western countries. The clinical course of delta hepatitis in general is associated with rapid progression. Delta hepatitis may be an additional risk factor for the development of hepatocellular carcinoma. The only established management for delta hepatitis consists of treatment with interferon for a period of at least one year. For those unresponsive to interferon treatment and patients with advanced disease new therapies are an urgent need. Such therapies may be on the horizon but translation of bench work to clinical practice is required.

In vitro autoradiography による慢性障害肝臨床例の核酸代謝異常に関する研究

in vitro autoradiography による慢性障害肝臨床例の核酸代謝異常に関する研究

Mass Spectrometric Characterization of Glycosylation of Hepatitis C Virus E2 Envelope Glycoprotein Reveals Extended Microheterogeneity of N-Glycans

Hepatitis C virus (HCV) causes acute and chronic liver disease in humans, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The polyprotein encoded in the HCV genome is co- and post-translationally processed by host and viral peptidases, generating the structural proteins Core, E1, E2, and p7, and five nonstructural proteins. The two envelope proteins E1 and E2 are heavily glycosylated. Studying the glycan moieties attached to the envelope E2 glycoprotein is important because the N-linked glycans on E2 envelope protein are involved in the interaction with some human neutralizing antibodies, and may also have a direct or indirect effect on protein folding. In the present study, we report the mass spectrometric characterization of the glycan moieties attached to the E2 glycoprotein. The mass spectrometric analysis clearly identified the nature, composition, and microheterogeneity of the sugars attached to the E2 glycopeptides. All 11 sites of glycosylation on E2 protein were characterized, and the majority of these sites proved to be occupied by high mannose glycans. However, complex type oligosaccharides, which have not been previously identified, were exclusively observed at two N-linked sites, and their identity and heterogeneity were determined.

Interaction between caspase-8 activation and endoplasmic reticulum stress in glycochenodeoxycholic acid-induced apoptotic HepG2 cells

The accumulation of hydrophobic bile acid, such as glycochenodeoxycholic acid (GCDCA), in the liver has been thought to induce hepatocellular damage in human chronic cholestatic liver diseases. We previously reported that GCDCA-induced apoptosis was promoted by both mitochondria-mediated and endoplasmic reticulum (ER) stress-associated pathways in rat hepatocytes. In this study, we elucidated the relationship between these pathways in GCDCA-induced apoptotic HepG2 cells. HepG2 cells were treated with GCDCA (100–500 μM) with or without a caspase-8 inhibitor, Z-IETD-fluoromethyl ketone (Z-IETD-FMK) (30 μM) for 3–24 h. We demonstrated the presence of both apoptotic pathways in these cells; that is, we showed increases in cleaved caspase-3 proteins, the release of cytochrome c from mitochondria, and the expression of ER resident molecular chaperone Bip mRNA and ER stress response-associated transcription factor Chop mRNA. On the other hand, pretreatment with Z-IETD-FMK significantly reduced the increases, compared with treatment with GCDCA alone. Immunofluorescence microscopic analysis showed that treatment with GCDCA increased the cleavage of BAP31, an integral membrane protein of ER, and pretreatment with Z-IETD-FMK suppressed the increase of caspase-8 and BAP31 cleavage. In conclusion, these results suggest that intact activated caspase-8 may promote and amplify the ER stress response by cleaving BAP31 in GCDCA-induced apoptotic cells.

Reply:

We thank Zamora-Valdes and colleagues for their note of caution. We agree completely that our results can not be extrapolated to humans. Nevertheless, they open the discussion on new medical treatments of liver cirrhosis. There are probably species-specific differences with respect to the dose of atorvastatin. For our study, we used a dosage of 15 mg/kg/day. An even higher dosage of atorvastatin1-3 has been used in rat models in the field of cardiovascular research. It is correct that serum cholesterol levels may be high in patients with cholestasis, especially in patients with primary biliary cirrhosis. Interestingly, serum cholesterol levels did not increase after bile duct ligation in our model (Bile duct ligation = 63.8 ± 5.6 versus controls = 66.2 ± 4.2 mg/dL). We understand the concerns with respect to a cholesterol-lowering therapy in patients with cirrhosis, although the points raised in the correspondence may appear a bit far-fetched. Yet all these issues, among others, have to be considered in case of planning a study on the application of statins to influence the course of chronic liver disease in humans. Such studies on drugs that potentially may influence liver cirrhosis and/or portal hypertension are certainly warranted because our armamentarium is limited. Jonel Trebicka M.D.*, Tilman Sauerbruch M.D.*, Jörg Heller M.D.*, * Department of Internal Medicine I, University of Bonn, Bonn, Germany.

The Complex Functions of Mast Cells in Chronic Human Liver Diseases

Mast cells (MCs) are multifunctional effector cells of the immune system. MCs were originally thought to be involved in IgE-associated immediate hypersensitivity and allergic disorders, but it is now known that they contain or elaborate an array of mediators with a multitude of effects on many other cells. A number of studies have found that MCs are involved in various liver diseases. Although still controversial, they seem to be involved in the liver's fibrotic response to chronic inflammation and parasitic infection. Hepatic fibrosis is the most frequent liver response to toxic, infectious, or metabolic agents. During the establishment of this pathological condition, there is an increase in the components of the basement membrane that leads to continuous basement membrane-like structures being raised within Disse's space and a decrease in the number of sinusoid endothelial fenestrae. This leads to a complex process called "sinusoidal capillarization." At the cellular level, liver fibrogenesis is initiated by hepatocyte necrosis, which induces the recruitment of a large number of inflammatory cells, including MCs, which can be considered the primary effectors of the process changing sinusoidal endothelial cells into capillary-type endothelial cells. We review the roles played by MCs in hepatic chronic diseases and describe a biopsy section of hepatic tissue taken from a patient with chronic C virus-related hepatitis showing diffuse sinusoidal capillarization and a high density of MCs. This observation has led us to hypothesize a relationship between these highly specialized cells and sinusoidal capillarization.