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The anti-tumoral activity of somatostatin has been demonstrated in both animal experiments and human tumors. Clinical trials have reported conflicting results. We therefore hypothesized that somatostatin might have different effects in various hepatocellular carcinoma cells. Their clarification would possibly allow for the better selection of patients suitable for the optimal treatment results. We studied the mRNA and protein expression of TNF receptors and the TNFa-induced apoptosis using the HepG2 and the Hep3B human hepatocellular carcinoma cells after incubation with the somatostatin analog octreotide. RT-PCR, Western blot, and parameters associated with apoptosis (NF-kB nuclear translocation, P65 Ser536 and P65 Ser468 phosphorylation, DNA fragmentation) were assessed. Only TNFR1 was constitutively present in the two cell lines. Octreotide incubation led to an earlier reduction in TNFR1 mRNA and protein in HepG2 compared to Hep3B cells (1 h and 6–12 h, respectively). NF-kB translocation to the nucleus was induced by TNFa and was more prominent in Hep3B. Translocation was unaffected by octreotide. Serine phosphorylation was significantly induced by TNFa and was more evident in the Hep3B cells. TNFa-induced Ser536 phosphorylation was inhibited by octreotide only in the HepG2 cells. DNA fragmentation was not influenced by either octreotide or TNFa in the HepG2 cells, but TNFa induced fragmentation in the Hep3B cells (1.8-fold increase) verified by the TUNEL index (43 compared to 19 for the HepG2 cells). Octreotide and TNFa co-incubation induced apoptosis in the HepG2 cells (1.7-fold increase compared to controls) but inhibited apoptosis in the Hep3B cells. We conclude that: (1) octreotide reduced TNFR1 receptor expression in both cell lines, (2) parameters of apoptosis were differentially affected by octreotide in the two cell lines, and (3) this might be a partial explanation for the conflicting results of somatostatin analog treatment in human hepatocellular carcinoma trials.

It is generally accepted that eradication of Helicobacter pylori (H. pylori) infection may reduce the risk of the development of gastric cancer. Recommendations for global generalized tests and treat all individuals detected positive for H. pylori infection are currently proposed. However, the bacterium is commensal and harmless for the vast majority of the infected population. Moreover, eradication may have detrimental consequences in several groups of patients. In the present review, the current epidemiological data and recommendations for eradication in connection with the possible beneficial effects of the colonization with H. pylori in diseases such as asthma and allergies or chronic gastro-intestinal disorders such as inflammatory bowel disease and Barrett’ esophagus are presented the problems with increasing antibiotic resistance were also examined. Specific groups of patients where eradication of H. pylori may be necessary and endoscopic surveillance is advised were identified. Finally, based on the paradox of high H. pylori prevalence and low gastric risk as reported for areas of Africa, Asia, South America, and Greece, alternatives that may replace the widespread eradication of H. pylori with equal if not better results and more prudent use of the available financial resources are proposed. Mediterranean diets and alcohol and smoking reduction are among the well documented alternatives.

The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.

The intestinal microbiota is closely related to liver diseases via the intestinal barrier and bile secretion to the gut. Impairment of the barrier can translocate microbes or their components to the liver where they can contribute to liver damage and fibrosis. The components of the barrier are discussed in this review along with the other elements of the so-called gut–liver axis. This bidirectional relation has been widely studied in alcoholic and non-alcoholic liver disease. However, the involvement of microbiota in the pathogenesis and treatment of viral liver diseases have not been extensively studied, and controversial data have been published. Therefore, we reviewed data regarding the integrity and function of the intestinal barrier and the changes of the intestinal microbioma that contribute to progression of Hepatitis B (HBV) and Hepatitis C (HCV) infection. Their consequences, such as cirrhosis and hepatic encephalopathy, were also discussed in connection with therapeutic interventions such as the effects of antiviral eradication and the use of probiotics that may influence the outcome of liver disease. Profound alterations of the microbioma with significant reduction in microbial diversity and changes in the abundance of both beneficial and pathogenic bacteria were found.

Extracellular vesicles (EVs) are bilayer vesicles released by cells in the microenvironment of the liver including parenchymal and non-parenchymal cells. They are the third important mechanism in the communications between cells, besides the secretion of cytokines and chemokines and the direct cell-to-cell contact. The aim of this review is to discuss the important role of EVs in viral liver disease, as there is increasing evidence that the transportation of viral proteins, all types of RNA, and viral particles including complete virions is implicated in the pathogenesis of both viral cirrhosis and viral-related hepatocellular carcinoma. The biogenesis of EVs is discussed and their role in the pathogenesis of viral liver diseases is presented. Their use as diagnostic and prognostic biomarkers is also analyzed. Most importantly, the significance of possible novel treatment strategies for liver fibrosis and hepatocellular carcinoma is presented, although available data are based on experimental evidence and clinical trials have not been reported.

The pathogenesis of inflammatory bowel disease (IBD) implicates several interconnecting factors. Immunity and external factors interact, and most aspects are still under investigation. Autophagy and apoptosis are two critical pathways that decide the fate of the individual cells of the intestinal mucosa. Experimental and clinical data indicate that the two are closely interconnected and usually mutually exclusive. However, despite the abundant information on their role, very limited translation into therapeutic application has been seen during recent years. In this review, research on these two pathways is presented. After a general overview of autophagy and apoptosis, their association with IBD, including the important mitophagy and ferroptosis, is discussed. The influence of autophagy- and apoptosis-related genes is also discussed. Finally, the interplay of autophagy and apoptosis in IBD is presented and the implications for treatment applications are examined. It is shown that dysregulated autophagy leads to increased apoptosis of enterocytes and impairs the tight junction proteins of the protective intestinal barrier. Dysregulated autophagy also induces the downregulation of lysozyme and the other antimicrobial proteins’ production. Mucus production by the goblet cells is also reduced due to defective autophagy and increased apoptosis.

The pathogenesis of primary biliary cholangitis (PBC) is particularly complicated as both intrinsic and extrinsic factors are implicated. Several forms of cellular death, both programmable and non-programmable, operate leading biliary epithelial cells (BECs) to elimination. The precise role of critical pathways like autophagy, apoptosis, senescence, and their interplay has not been fully clarified. Therefore, in this review, data on these important mechanisms are presented and their implication in PBC is discussed. The interplay of the three mechanisms is examined and the factors that drive them are analyzed. Moreover, the upstream drivers of autophagy, apoptosis, and senescence are presented. They include the loss of the protective bicarbonate umbrella in BECs due to the reduction of activity of the anion exchanger 2 (AE2) with the resultant activation of the intracellular soluble adenylyl cyclase (sAC). The role of toxic bile acids is also presented. A sequence of events is proposed including involvement of the gut-liver axis and the possible role of ferroptosis. Finally, a brief account of the initial trigger of the disease is given.

Patients with advanced hepatocellular carcinoma (HCC) have a very limited survival rate even after the recent inclusion of kinase inhibitors or immune checkpoint inhibitors in the therapeutic armamentarium. A significant problem with the current proposed therapies is the considerable cost of treatment that may be a serious obstacle in low- and middle-income countries. Implementation of somatostatin analogues (SSAs) has the potential to overcome this obstacle, but due to some negative studies their extensive evaluation came to a halt. However, experimental evidence, both in vitro and in vivo, has revealed various mechanisms of the anti-tumor effects of these analogues, including inhibition of cancer cell proliferation and angiogenesis and induction of apoptosis. Favorable indirect effects such as inhibition of liver inflammation and fibrosis and influence on macrophage-mediated innate immunity have also been noted and are presented in this review. Furthermore, the clinical application of SSAs is both presented and compared with clinical trials of kinase and immune checkpoint inhibitors (ICIs). No direct trials have been performed to compare survival in the same cohort of patients, but the cost of treatment with SSAs is a fraction compared to the other modalities and with significantly less serious side effects. As in immunotherapy, patients with viral HCC (excluding alcoholics), as well as Barcelona stage B or C and Child A patients, are the best candidates, since they usually have a survival prospect of at least 6 months, necessary for optimum results. Reasons for treatment failures are also discussed and further research is proposed.

The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.

Introduction: Liver fibrosis has been extensively studied at the cellular and molecular level, but very few data exist on the final enzymatic stages of collagen synthesis (prolyl hydroxylase, PH) and degradation (matrix metalloproteinases, MMPs), particularly in primary biliary cholangitis (PBC). Aim: We studied enzyme activities in liver tissue from patients with chronic liver diseases and compared them to normal livers. Patients: Eighteen patients with PBC of early and late stages (Ludwig’s classification) and seven on treatment with ursodeoxycholate (UDCA) were studied and compared to 34 patients with alcoholic liver disease (ALD), 25 patients with chronic viral liver disease and five normal biopsies. Sera were available from a total of 140 patients. Methods: The tritiated water released from the tritiated proline was measured in PH assessment. 14C intact and heat-denatured collagen substrates were used to measure collagenase and gelatinases, respectively. 3H Elastin was the substrate for elastase. In serum, ELISAs were used for MMP-1, TIMP-1, and TIMP-2 measurements while MMP-2 and MMP-9 were estimated by zymography. Results: PH was significantly increased in early and late PBC. Collagenase was reduced only in the late stages (p < 0.01), where the ratio PH/collagenase was increased. UDCA treatment restored values to almost normal. Gelatinases were reduced in late stages (p < 0.05). In contrast to PBC and ALD fibrosis, collagen synthesis is not increased in viral fibrosis. The balance shifted towards collagen deposition due to reduced degradation. Interestingly, gelatinolytic activity is not impaired in ALD. Elastase was similar to controls in all diseases studied. TIMP-1 was reduced in early PBC and viral and alcoholic hepatitis and cirrhosis (p < 0.001). Conclusions: (1) There is evidence that collagen synthesis increases in the early stages of PBC, but the collagenolytic mechanism may compensate for the increased synthesis. (2) In viral disease, fibrosis may be due to decreased degradation rather than increased synthesis. (3) The final biochemical stages of liver fibrosis may be quantitatively different according to underlying etiology.

Aim. To study the expression of angiodrastic chemokines in colorectal tumors and correlate findings with clinicopathological parameters and survival. Methods. The proangiogenic factor VEGF, the angiogenic chemokines CXCL8 and CXCL6, and the angiostatic chemokine CXCL4 were measured by ELISA in tumor and normal tissue of 35 stage II and III patients and correlated with the histopathology markers Ki67, p53, p21, bcl2, EGFR, and MLH1 and 5-year survival. The Wilcoxon and chi-square tests were used for statistical comparisons. Results. There was a significant increase of CXCL6 (p=0.005) and VEGF (p=0.003) in cancerous tissue compared to normal. Patients with lower levels of CXCL8 and CXCL4 lived significantly longer. Patients with loss of EGFR expression had higher levels of CXCL8 while p21 loss was associated with higher levels of CXCL6. Chemokine levels were not correlated with TNM or Dukes classification. Strong expression of p53 was accompanied by decreased survival. Conclusions. (1) The angiogenic factors CXCL6 and VEGF are increased in colorectal cancer tissue with no association with the clinical stage of the disease or survival. (2) However, increased levels of tissue CXCL8 and CXCL4 are associated with poor survival. (3) Strong expression of p53 is found in patients with poor survival.

Abstract  Nitric oxide (NO) and Monocyte Chemoattractant Protein (MCP)-1 co-regulation has been found in endotoxin-activated macrophages. Kupffer cells (KC) are a main source of soluble-mediators production in liver abnormalities. We investigated in vitro similar co-regulation of NO and MCP-1 production in rat activated KC. Isolated rat KC were cultured in the presence of 1 μg/ml LPS and various concentrations of Wortmannin (0–300 nM), L-NAME (0–500 μM) or MCP-1 (0–100 ng/ml). Production of MCP-1 and NO were measured in supernatants, by ELISA and a modification of the Griess reaction, respectively. Growth arrested KC, stimulated with vehicle, produced a basal amount of NO and MCP-1. In the presence of LPS, cultured KC secreted significantly (P P P r = 0.59171, P r = 0.9215, P = 0.009) treated groups, but not in the L-NAME (r = −0.08513, P = 0.873). Incubation of KC with various concentrations of MCP-1 did not increase the NO production. These results indicate that KC might be the main source of NO and MCP-1 production in liver disorders, probably through the induction of PI3-kinase(s) and without any co-regulation between these molecules, which might represent two independent immunoregulatory pathways in the role of KC in hepatic disorders. [ABSTRACT FROM AUTHOR]

Abstract Introduction  Mannose-binding lectin (MBL) is involved in host’s response to several infections including hepatitis B but little is known about MBL and hepatitis C virus (HCV) infection. The present study attempts to investigate whether MBL2 genotype and serum MBL levels affect the course of HCV infection. Results and Discussions  We investigated the variant alleles in MBL2 gene promoter and exon-1 regions in 80 Caucasian HCV-infected patients. Mutations in MBL2 were determined by polymerase chain reaction and restriction fragment length polymorphisms analysis. Serum MBL levels were measured by ELISA. Polymorphism homozygosity in exon-1 region was significantly related to lower serum MBL levels (p p = 0.034, OR = 11.7) and, in a lesser degree, to fibrosis. Polymorphisms in promoter sites −221nt and −550nt were not shown to be related with serum MBL levels or progress to liver inflammation and fibrosis. Serum MBL levels were adversely associated with progression to fibrosis (p = 0.037). Response to antiviral treatment was related to hepatitis C virus genotype (p MBL2 genotype or serum MBL levels. Conclusion  These findings suggest that polymorphisms in MBL2 gene exon-1 region are related to low serum MBL levels and progression of HCV infection to liver inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Abstract  Somatostatin (SST) acts as an inhibitory peptide of various secretory and proliferative processes. Apart from neuroendocrine tumors, where SST analogues have an established role, they have been tested in other tumors such as hepatocellular carcinoma (HCC) in the view of the fact that chemotherapy is not working. Several positive reports have been published. Approximately 40% of patients respond with improved survival and an impressive quality of life. A usual misunderstanding in trial designs is that, although SST is not a rescue drug, selection of patients is inappropriate, with mostly moribund patients being recruited. SST analogues do not seem to work in 60% of HCCs and this has been linked to the presence of SST receptors (SSTR) in the tumor, while several resistance mechanisms might be involved. Future management should engage more specific SST analogues targeted to a tumor with a known SSTR map. The use of somatostatin analogues as an adjunct therapy in combination with other treatment modalities should also be investigated. [ABSTRACT FROM AUTHOR]

Pancreatic autoantibodies (PAbs) have been suggested as a specific but not sensitive marker for Crohn's disease (CD). The aim of this study was to assess the value of detecting PAbs in Greek patients with ulcerative colitis (UC) and CD. Sera were collected from 150 patients with IBD (73 with UC and 77 with CD), 31 cases with non-IBD intestinal inflammation, 16 cases with other autoimmune diseases, and 104 healthy controls. Determination of PAbs was performed by a standard indirect immunofluorescence technique. PAbs were detected in 18 of 73 (24.7%) samples from UC patients and in 32 of 77 (41.6%) samples from CD patients. The prevalence of positive PAbs was significantly higher in CD than in UC (P= 0.04). None of the 104 samples from healthy controls and the 31 cases with non-IBD intestinal inflammation had detectable PAbs. One patient with Sjogren's syndrome was PAbs positive. No association of PAbs with IBD activity, IBD localization, or medical treatment was found. Patients with stenotic CD had a significantly higher prevalence of PAbs positivity (60%) compared with patients with inflammatory (28.6%) and fistulizing (41.2%) disease (P= 0.02). The prevalence of PAbs in Greek CD patients was found to be similar to that in previous reports. In contrast to these studies we found also increased prevalence of PAbs in UC patients. These findings suggest that PAbs should be considered as a specific marker for IBD rather than for CD. [ABSTRACT FROM AUTHOR]

Abstract Kupffer cells may be involved in liver fibrogenesis through production of TGF-ß1. Their role in fibrinolysis is less clear. Octreotide, a synthetic analogue of somatostatin, is often used in cirrhotic patients. Its effect on Kupffer cells was studied. Isolated rat Kupffer cells were cultured in the presence of lipopolysaccharide and/or octreotide. TGF-ß1, leptin, collagenase (MMP-1), and urokinase-type plasminogen activator (uPA) were assessed in supernatants by ELISA, and MMP-2 and MMP-9 by zymography. Kupffer cells produced large amounts of MMP-1 and lipopolysaccharide induced a significant (P < 0.02) early increase. Octreotide and lipopolysaccharide caused a synergistic effect on MMP-1 secretion. By contrast, MMP-9 production stimulated by lipopolysaccharide was suppressed by octreotide. Kupffer cells produced a basal amount of uPA, significantly increased after lipopolysaccharide or octreotide incubation (P < 0.001). Large amounts of TGF-ß1 were produced in a time-dependent manner by unstimulated Kupffer cells. Lipopolysaccharide and octreotide, alone or in combination, induced a significant inhibition of this production (P < 0.01). Kupffer cells did not produce leptin, a recently identified mediator of liver fibrosis, or MMP-2. Kupffer cells may play a significant role in liver fibrinolysis. Octreotide, acting on TGF-ß1, uPA, and MMP-1 production, may be a useful agent for fibrosis resolution. [ABSTRACT FROM AUTHOR]

Angiogenesis-promoting cytokines have been suggested to play an important role in inflammatory bowel disease (IBD) since they promote inflammation by increasing vascular permeability and mediate tissue repair by activating fibroblasts. The aim of the present study was to evaluate the serum levels of angiogenin, a potent angiogenic factor, in patients with ulcerative colitis (UC) and Crohn’s disease (CD). Angiogenin serum levels were measured in 154 IBD patients (78 UC and 76 CD), in 18 cases with other causes of intestinal inflammation, and in 84 matched healthy controls using a commercially available enzyme-linked immunosorbent assay. Angiogenin levels were assessed in terms of disease activity, type, localization, and treatment. Mean (±SD) serum angiogenin levels were 526.5 ± 224.1 ng/ml in UC patients, 508.8 ± 228.5 ng/ml in CD patients, 394.6 ± 137.6 ng/ml in healthy controls, and 448.1 ± 167.8 ng/ml in patients with non-IBD intestinal inflammation. A statistically significant difference among the mean levels of angiogenin in the four groups was found (P=0.0003). IBD patients with early disease had a significantly lower mean serum angiogenin compared with patients with late disease (P=0.03). No significant association between angiogenin levels and disease activity, localization, disease type, or treatment was found. Serum angiogenin is elevated in patients with IBD. The increased serum angiogenin suggests that angiogenin may mediate angiogenesis and vascular permeability in the mucosa of patients with IBD. [ABSTRACT FROM AUTHOR]

Background: The existence of reliable prognostic indices is of paramount importance in the management of cirrhosis. Both the model for end-stage liver disease (MELD) score and the older Child-Pugh (CP) scores are widely used. The albumin-bilirubin (ALBI) score, initially used in hepatocellular carcinoma, has not been thoroughly investigated in cirrhosis. The aim of this study was to compare the prognostic accuracy of ALBI, MELD, MELD with sodium (MELD-Na), CP, and the corrected for creatinine CP scores in a genetically homogeneous Cretan cirrhotic population., Methods: One hundred ninety-five outpatients or hospitalized cirrhotics (127 male, median age 66 years) were studied over a period of 2 years and ALBI, platelet-albumin-bilirubin, MELD, MELD-Na, CP score, and 2 types of modified CP score (CP-I and CP-II) with serum creatinine were calculated and correlated with survival., Results: ALBI had an optimum balance between sensitivity and specificity (area under the curve 0.704, 95% confidence interval [CI] 0.630-0.778) compared to the other scores. In the multivariate analysis, the only factors independently associated with death were the ALBI score (hazard ratio [HR] 2.51, 95%CI 1.69-3.73; P<0.001), the MELD-Na score (HR 1.04, 95%CI 1.00-1.09; P=0.045), and age (HR 1.05, 95%CI 1.03-1.07; P<0.001). When only decompensated cirrhosis was evaluated, the multivariate analysis showed that the ALBI score (HR 3.03; 95%CI 1.92-4.78; P<0.001), and age (HR 1.05, 95%CI 1.03-1.07; P<0.001) were independently associated with death., Conclusion: ALBI score might be a better prognostic indicator of mortality in cirrhosis and given its simplicity could substitute for the CP, MELD, and MELD-Na scores., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Primary biliary cirrhosis (PBC) is a chronic non-suppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient's genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated. A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed.

Aim: To investigate the presence of autoantibodies directed against liver sinusoidal cells in primary biliary cirrhosis (PBC)., Methods: Liver biopsies from 21 PBC patients were studied and compared with 12 liver biopsies from disease controls [3 patients with hepatitis B (HBV) virus, 3 patients with hepatitis C virus (HCV), 3 patients with non-alcoholic steatohepatitis and 3 patients with acute alcoholic hepatitis (AAH)]. As healthy controls, we used tissue specimens adjacent to metastatic liver adenocarcinoma. Normal serum was taken from staff members of the unit. The determination of the cell type targeted by autoantibodies present in the patients sera was performed by indirect immunofluorescence (IIF) analysis using paraffin-embedded liver sections as a substrate. Sera from homologous or heterologous PBC patients or sera from the disease control group were used as primary antibodies. The presence of autoantibodies was identified using confocal microscopy., Results: In total, 18/21 (85.7%) PBC patients exhibited positive staining in the sinusoidal cells, 10/21 (47.6%) in lymphocytes, 8/21 (38%) in cholangiocytes and 7/21 (33.3%) in hepatocytes, when homologous serum and fluorescein isothiocyanate-conjugated immunoglobulin type G (IgG) secondary antibody were used. PBC sections incubated with heterologous PBC serum showed reduced staining (20% for sinusoidal cells, 20% for lymphocytes, 20% for cholangiocytes and 13.3% for hepatocytes). When IgM immunoglobulin, instead of IgG, was used as secondary antibody, positive staining was observed in 75% of lymphocytes, 62.5% of cholangiocytes, 37.5% of hepatocytes and 50% of the sinusoidal cells with a much stronger staining intensity. No staining was observed when either normal or PBC sera were used as a primary antibody on liver sections from the disease control group. When PBC sera were incubated with healthy control sections, weak positive staining of cholangiocytes was observed in 3/21 (14.3%) PBC serum samples. Steatohepatitis serum on PBC sections gave a positive staining of some hepatocytes and lymphocytes but no staining on viral hepatitis sections. Incubation with HBV sera stained some hepatocytes, cholangiocytes and intra-sinusoidal or portal lymphocytes of PBC, HBV and AAH patients but not HCV patients., Conclusion: In this study, for the first time in diseased liver tissue, we have demonstrated that a large proportion of PBC patients have disease specific autoantibodies against liver sinusoidal cells.