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Platelets contain not only proteins needed for hemostasis but also many growth factors that are required for organ development, tissue regeneration, and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, is due to various causes, such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in CLD are poorly understood. Thus, in this paper, the experimental evidence for platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. Platelets improve liver fibrosis by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cAMP is increased by adenosine through its receptors on hepatic stellate cells, thereby resulting in inactivation of these cells. Adenosine is produced by degradation of adenine nucleotides, which are stored in abundance within the dense granules of platelets. The regenerative effect of platelets in the liver consists of three mechanisms: a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these experiments, a clinical trial suggested that the increase in platelets induced by platelet transfusion improved liver function in patients with CLD in a clinical setting.We highlight the current knowledge concerning the role of platelets in CLD and expect to open a novel avenue for application of these clinical therapies to treat liver disease. [ABSTRACT FROM AUTHOR]

This paper, the second in the series, will build on the first and explore the importance of liver and pancreatic manifestations of cystic fibrosis ( CF) and the effect on morbidity and mortality of this multifaceted genetic condition. It will also further develop the critical role of the gastroenterologist as part of the multidisciplinary group of clinicians and allied health staff in the effective management of patients with CF. [ABSTRACT FROM AUTHOR]

Background: Steatosis occurs frequently in hepatitis C. However, the mechanisms leading to this lesion are still unknown, and the role of steatosis in the progression of the disease remains controversial. The aim of the present paper was to determine the prevalence of steatosis in hepatitis C and its association with hepatitis C virus (HCV) genotype, viral load and the presence of risk factors for steatosis, and to analyze the association between steatosis and the intensity of liver disease. Methods: Patients infected with HCV who underwent liver biopsy were included. Patients coinfected with hepatitis B virus and/or human immunodeficiency virus and those previously treated for hepatitis C were excluded. The following risk factors for steatosis were investigated: obesity (body mass index [BMI] > 25 kg/m2), diabetes mellitus, hyperlipidemia, alcoholism, and use of potential steatosis-inducing drugs. Histological analysis evaluated the presence of steatosis, the degree of periportal activity and staging. Patients with and without steatosis were compared regarding demographic, epidemiological, laboratory and histological characteristics. Logistic regression analysis was applied to identify variables that were independently associated with the presence of steatosis. Results: Ninety patients (55 men, 35 women) with a mean age of 45 ± 13 years were included. The prevalence of steatosis was 67%. Variables that remained independently associated with steatosis were age, female gender, obesity and genotype 3. Conclusions: The prevalence of steatosis in hepatitis C was high. Risk factors usually related to steatosis such as age, female gender and obesity, as well as genotype 3, were independently associated with the presence of steatosis. Steatosis was not independently associated with the intensity of histological liver disease. [ABSTRACT FROM AUTHOR]

The present paper provides a brief overview of the rationale behind magnetic resonance imaging (MRI) techniques, a description of the most common sequences used, and a general approach to performing liver MRI. [ABSTRACT FROM AUTHOR]

Liver diseases are associated with the leaky gut via the gut‐liver‐axis. Previous studies have paid much attention to the effect of gut barrier damage. Notably, clinical observations and basic research reveal that the gut barrier damage seldom leads to liver injury independently but aggravates pre‐existing liver diseases such as non‐alcoholic fatty liver disease and drug‐induced liver injury. These evidences suggest that there is a hepatic barrier in the gut‐liver‐axis, protecting the liver against gut‐derived pathogenic factors. However, it has never been investigated which type of liver cell plays the role of hepatic barrier. Under physiological conditions, liver sinusoidal endothelial cell (LSEC) can take up and eliminate virus, bacteriophage, microbial products, and metabolic wastes. LSEC also keeps the homeostasis of liver immune environment via tolerance‐inducing and anti‐inflammatory functions. In contrast, under pathological conditions, the clearance function of LSEC is impaired, and LSEC turns into a pro‐inflammatory pattern. Given its anatomical position and physiological functions, LSEC is proposed as the hepatic barrier in the gut‐liver‐axis. In this review, we aim to further understand the role of LSEC as the hepatic barrier. Future studies are warranted to seek effective treatments to improve LSEC health, which appears to be a promising approach to prevent gut‐derived liver injury. [ABSTRACT FROM AUTHOR]

Background and Aim: Cardiovascular disease (CVD) is the principal cause of death in patients with type 2 diabetes (T2D). In this study, we assessed whether liver fibrosis predicted the risk of CVD in patients with T2D. Methods: A total of 1481 patients who had commenced oral antidiabetic drugs to treat newly diagnosed T2D between 2006 and 2010 were recruited. The fibrosis‐4 index (FIB‐4), non‐alcoholic fatty liver disease fibrosis score (NFS), and BARD score were used to assess fibrotic burden at the time of T2D diagnosis. Results: During the follow‐up period (median 88.1 [interquartile range 36.6–113.6] months), 242 (16.3%) patients developed CVD. CVD occurred frequently in older patients and was associated with hypertension; metabolic syndrome; obesity; smoking; administration of statin, which is an antihyperlipidemic drug; lower platelet counts; lower alanine aminotransferase, total cholesterol, and HbA1c levels; higher C‐peptide and homeostatic model assessment of insulin resistance levels; and higher FIB‐4, NFS, and BARD score (all P < 0.05). FIB‐4 (hazard ratio [HR] = 1.163), NFS (HR = 1.322), BARD score (HR = 1.564), metabolic syndrome (HR = 1.556), smoking (HR = 2.829), and statin use (HR = 0.603) independently predicted the risk of CVD (all P < 0.05). The cumulative incidence of CVD was significantly different among groups stratified by liver fibrotic burden (all P < 0.05, log‐rank test). Competing risk analysis showed a significant association between the severity of liver fibrosis and CVD development (all P < 0.001, Gray's test). Conclusions: The severity of liver fibrosis independently predicted CVD in patients with T2D. Thus, assessment of liver fibrosis might allow physicians to optimize the timing of appropriate cardiovascular interventions in such patients. [ABSTRACT FROM AUTHOR]

The advancement of investigation tools and electronic health records (EHR) enables a paradigm shift from guideline‐specific therapy toward patient‐specific precision medicine. The multiparametric and large detailed information necessitates novel analyses to explore the insight of diseases and to aid the diagnosis, monitoring, and outcome prediction. Artificial intelligence (AI), machine learning, and deep learning (DL) provide various models of supervised, or unsupervised algorithms, and sophisticated neural networks to generate predictive models more precisely than conventional ones. The data, application tasks, and algorithms are three key components in AI. Various data formats are available in daily clinical practice of hepatology, including radiological imaging, EHR, liver pathology, data from wearable devices, and multi‐omics measurements. The images of abdominal ultrasonography, computed tomography, and magnetic resonance imaging can be used to predict liver fibrosis, cirrhosis, non‐alcoholic fatty liver disease (NAFLD), and differentiation of benign tumors from hepatocellular carcinoma (HCC). Using EHR, the AI algorithms help predict the diagnosis and outcomes of liver cirrhosis, HCC, NAFLD, portal hypertension, varices, liver transplantation, and acute liver failure. AI helps to predict severity and patterns of fibrosis, steatosis, activity of NAFLD, and survival of HCC by using pathological data. Despite of these high potentials of AI application, data preparation, collection, quality, labeling, and sampling biases of data are major concerns. The selection, evaluation, and validation of algorithms, as well as real‐world application of these AI models, are also challenging. Nevertheless, AI opens the new era of precision medicine in hepatology, which will change our future practice. [ABSTRACT FROM AUTHOR]

Recently, radiomics and deep learning have gained attention as methods for computerized image analysis. Radiomics and deep learning can perform diagnostic or predictive tasks using high‐dimensional image‐derived features and have the potential to expand the capabilities of liver imaging beyond the scope of traditional visual image analysis. Recent research has demonstrated the potential of these techniques in various fields of liver imaging, including staging of liver fibrosis, prognostication of malignant liver tumors, automated detection and characterization of liver tumors, automated abdominal organ segmentation, and body composition analysis. However, because most of the previous studies were preliminary and focused mainly on technical feasibility, further clinical validation is required for the application of radiomics and deep learning in clinical practice. In this review, we introduce the technical aspects of radiomics and deep learning and summarize the recent studies on the application of these techniques in liver radiology. [ABSTRACT FROM AUTHOR]

Background and Aim: Imaging noradrenergic uptake in the liver with norepinephrine analog 123I‐meta‐iodobenzylguanidine (mIBG) was explored in normal controls and patients with heart failure (HF). Methods: A total of 961 HF (343 with diabetes mellitus [DM]) and 94 control subjects underwent anterior planar mIBG images including upper abdomen at 15 min (early) and 3 h 50 min (late) post‐injection. Decay‐corrected liver activity normalized to injected activity and body surface area (counts/pixel [cpp]/MBq/m2) was compared in three groups: HF with DM; HF without DM; and controls. Associations with plasma norepinephrine, liver function tests, and level of cardiac innervation were explored. Results: In controls, liver mIBG activity decreased over time (early: 2.78 vs late: 2.43 cpp/MBq/m2, P < 0.0001); in HF subjects, activity increased during this interval (HF without DM: 2.85 vs 2.93 [P = 0.005]; HF with DM: 2.37 vs 2.43 [P = 0.054]). Early liver activity was lower in HF with DM subjects than in the other groups (P < 0.001); late liver activity was higher in HF without DM than in the other two groups (P < 0.01). Subjects with elevated plasma norepinephrine (> 520 pg/mL) or ≥ 1 abnormal liver function test had lower early and late liver activity. In subjects with preserved cardiac mIBG uptake, HF subjects had higher and control subjects lower liver activity than comparable subjects with decreased cardiac innervation. Conclusions: In HF subjects, liver mIBG activity increased over time, reversing the normal washout pattern, suggesting a compensatory change in sympathetic nerve function. DM, abnormal liver function tests, and decreased cardiac innervation were associated with decreased liver mIBG uptake in HF. [ABSTRACT FROM AUTHOR]

Liver stiffness measurement (LSM) by FibroScan‐determined transient elastography is a noninvasive approach to estimate liver fibrosis severity. In non‐alcoholic fatty liver disease (NAFLD), advanced liver fibrosis is excluded by normal liver stiffness, but a wide range of cutoffs have been used to predict advanced liver fibrosis or cirrhosis. This may be partly because steatosis (measured by controlled attenuation parameter [CAP]) contributes to liver stiffness and also because LSM fluctuates in NAFLD. In a recent pivotal study, one‐third of patients with liver stiffness > 12.0 kPa showed reversal after 4–6 months; these cases did not have advanced liver fibrosis on biopsy. We performed serial FibroScans 6–36 months apart in 73 NAFLD patients, 38 with LSM > 10 kPa at entry. Those who lost ≥ 1 kg of weight (n = 31) significantly reduced liver stiffness (3.6 ± 6.1 vs 0.53 ± 4.1 kPa, P < 0.05) and CAP score (39 ± 63 dB/m of loss vs 24 ± 65 dB/m of gain, P < 0.05) compared with those who did not (n = 29). Patients who reported increased physical activity (n = 25) also reduced liver stiffness (3.6 ± 6 vs 0.35 ± 6 kPa) and CAP (20 ± 71 dB/m of loss vs 32 ± 71 dB/m of gain). Overall, those with improved LSM were significantly more likely to have lost weight and/or improved physical activity. These effects of lifestyle adjustments partly explain why a single measurement of 12.0 kPa is not a reliable cutoff for advanced liver fibrosis in NAFLD. In addition to repeating the study after 6–12 months, documentation of response to lifestyle advice and weight reduction should be determined before assuming any cutoff indicates advanced liver fibrosis. Despite this reservation about diagnostic accuracy, we consider that measurement of liver stiffness and CAP score serve to motivate patients to enact lifestyle modifications that can improve NAFLD severity. [ABSTRACT FROM AUTHOR]

Background: Hepatic fibrosis is the final endpoint for most chronic liver diseases and remains a significant public health problem worldwide. Icariin, a naturally occurring flavonol glucoside, has been reported to exhibit protective effects on liver injury and alleviate liver fibrosis. However, the underlying detail molecular mechanism is not fully revealed. Methods: Mouse primary hepatic stellate cells (HSCs) and carbon tetrachloride (CCL4)‐induced liver fibrosis model in mice were used as in vitro and in vivo models in this study. The expression levels of miR‐875‐5p were detected by quantitative reverse transcription‐PCR. The validation of the direct target of miR‐875‐5p was through dual‐luciferase reporter assay and western blotting assay. The cell proliferation and cell mobility were determined using MTT assay and Transwell migration assay, respectively. Results: We found that icariin inhibited epithelial–mesenchymal transition and collagen protein section of HSCs. Icariin exerted hepatoprotective effects on mice model of CCL4‐induced liver fibrosis. Our further results revealed that miR‐875‐5p was downregulated in human cirrhosis tissues and activated murine HSCs. Icariin induced miR‐875‐5p upregulation and subsequently decreased glioma‐associated oncogene homolog 1 (GLI1) expression through direct binding to the three prime untranslated region of GLI1 mRNA. Conclusion: Our study highlighted the potential therapeutic application of icariin for liver fibrosis management. [ABSTRACT FROM AUTHOR]

Background and Aim: Massive hepatic necrosis is a rare but often fatal complication of various liver injuries. Nevertheless, some patients can survive by spontaneous hepatic regeneration. It is known that surviving hepatocytes and/or progenitor cells can participate in this process but the mechanism of hepatic recovery is vague. Methods: We examined 13 explanted human livers removed for acute liver failure. Combined immunohistochemistry, digital image analysis, and three‐dimensional reconstruction of serial sections were applied. Results: Two patterns of regeneration could be distinguished. In livers with centrilobular necrosis, the surviving injured periportal hepatocytes started to proliferate and arrange into acinar structures and expressed α‐fetoprotein. If the injury wiped out almost all hepatocytes, large areas of parenchymal loss were invaded by an intense ductular reaction. The cells at the distal pole of the ductules differentiated into hepatocytes and formed foci organized by the branches of the portal vein. The expanding foci often containing complete portal triads were arranged around surviving central veins. Their fusion eventually could be an attempt to re‐establish the hepatic lobules. Conclusions: Regeneration of human livers following massive hepatic necrosis can occur in two ways—either through proliferation of α‐fetoprotein‐positive acinary‐arranged hepatocytes or through ductular progenitor cells, with the latter being less efficient. Further investigation of these regenerative pathways may help identify biomarkers for likelihood of complete regeneration and hence have therapeutic implications. [ABSTRACT FROM AUTHOR]

Highlights the 2002 annual congress of the Asian Pacific Association for the Study of the Liver. Progress in the field of medicine and science in viral hepatitis.

Abstract: The concept of consuming microorganisms in the treatment of a medical condition and in health maintenance has gained much attraction, giving rise to an abundance of medical claims and of health supplements. This study identified relevant clinical questions on the therapeutic use of probiotics and reviewed the literature in irritable bowel syndrome, inflammatory bowel disease, impaired intestinal immunity, liver disease, intestinal infections, and common childhood digestive disorders. Statements were developed to address these clinical questions. A panel of experienced clinicians was tasked to critically evaluate and debate the available data. Both consensus and contentious statements are presented to provide to clinicians a perspective on the potential of probiotics and importantly their limitations. [ABSTRACT FROM AUTHOR]

Background and Aim The usefulness of carcinoembryonic antigen ( CEA) in the diagnosis and prognosis of colorectal cancer ( CRC) is unclear. The aim was to analyze changes in the expression of CEA during CRC progression and metastasis, so as to determine the influence of tumor metastatic organ on the CEA expression by CRC cells. Methods The human biopsies of adenocarcinomas in colon and CRC liver and lung metastases were analyzed by immunohistochemistry for the expression of CEA. Expression of E-cadherin and β-catenin was also analyzed to localize the CRC neoplastic glands in metastatic tissues. Results The CRC neoplastic glands in colon and liver expressed significantly higher amount of CEA compared with crypts in normal colon. In contrast, CRC neoplastic glands formed in lung expressed low CEA level. However, CEA expression was high in areas of tumor necrosis in lung. E-cadherin and β-catenin were cell membrane-bound in normal crypts and CRC neoplastic glands in colon and liver. Although these two proteins were also cell membrane-bound in a majority of CRC neoplastic glands in lungs, a significant proportion of these expressed β-catenin in the nucleus, which lacked either E-cadherin or β-catenin at the cell membrane. Conclusion Our findings indicate that lung microenvironment is unique in that it suppresses the expression of CEA by CRC cells forming neoplastic glands. In addition, lung microenvironment promotes nuclear localization of β-catenin, suggesting that the Wnt signaling pathway is relatively active highly in CRC metastasized to lung, when compared with liver or colon. [ABSTRACT FROM AUTHOR]

The article presents abstracts of articles related to clinical hepatology which include "Nurse assessment clinic: an efficient and effective delivery of hepatitis C virus (HCV) assessment and review," by Marian L. Biddle and colleagues, and "Lessons learnt: implementation of transient elastography as a routine clinical service," by Marrianne Black and colleagues, and "Liver stiffness as a novel marker of metabolic syndrome?," by Eng K. Gan and colleagues.

The article presents abstracts on medical topics including the therapeutic use of imidazolium salts as anti-liver fibrosis, hepatorenal syndrome prevention in patients having cirrhosis, and the electromagnetic thermoablation to treat thrombocytopenia in cirrhotic and hypersplenic rats.

Background and Aims: A mechanism for protection of gastrointestinal (GI) and hepatic cells from damaging detergent actions of bile acids appears to involve the bile component, phosphatidylcholine (PC). Non-steroidal anti-inflammatory drugs (NSAIDs) induce intestinal injury in direct proportion to their ability to be excreted into bile, and are known to chemically associate with PC. We investigated the role of bile acids and PC in the mechanism of indomethacin-induced epithelial injury. Methods: Rats were injected orally or intravenously with radiolabeled indomethacin and their bile was collected over time for determination of NSAID secretion. Bile from rats treated with or without indomethacin was used in studies of red blood cell (RBC) hemolysis as a measure of membrane cytotoxicity. The bile salt, sodium deoxycholate (SDC), and indomethacin were tested alone and in combination with PC on RBC and on hepatic HepG2 cells. Results: Intravenously or orally given indomethacin was quantitatively excreted (approximately 50%) into bile over a 2-h study period. Bile from a rat treated with indomethacin or bile with exogenous indomethacin was cytotoxic to RBC, and the injury was prevented by the addition of PC. Hepatocytes exposed to SDC showed injury that could be dose-dependently prevented by PC, and reversed by indomethacin. Conclusions: Biliary PC plays an important physiological role in protecting GI and hepatic epithelia from the cytotoxic actions of bile salts. The ability of NSAIDs excreted into the bile to associate with mixed bile salt micelles and reduce the protective action of the PC may be a critical component in the drugs' pathogenic mechanism. [ABSTRACT FROM AUTHOR]

A 26-year-old, HLA-B27 positive man with steroid dependent Crohn's disease presented with abdominal lymphadenopathy and multiple abscess-like masses in the spleen and liver 2 years after the initial diagnosis. A biopsy of one of the liver lesions showed epitheloid cell granuloma, no microorganisms were detected despite intensive investigations. The liver lesions and the lymphadenopathy repeatedly disappeared completely in response to prednisolone pulse therapy while the lesions in the spleen remained practically unchanged. One year later, on immunosuppressive therapy with azathioprine and low-dose prednisolone, the patient's condition exacerbated with development of fever, disseminated arthritides and enlargement of the splenic lesions. Following ineffective antimicrobial treatment, a splenectomy was carried out. Histology showed that the splenic parenchyma was filled with abacterial, rheumatoid granulomas. After a renewed flare-up of severe extraintestinal symptoms, the patient is now asymptomatic on immunosuppressive therapy with azathioprine and prednisolone. Abdominal lymphadenopathy is no longer present and the liver lesions are regressing. The intermittent course and the positive response to immunosuppressive therapy point to a further extraintestinal manifestation of Crohn's disease. [ABSTRACT FROM AUTHOR]

Needle liver biopsy is essential for the diagnosis of liver fibrosis and cirrhosis. However, sampling variability has been reported by semiquantitative methods. The aim of the present study was to investigate quantitatively the sampling variability of needle liver biopsy on the assessment of liver fibrosis/cirrhosis.Liver samples of 12 patients undergoing autopsy, liver transplantation, or liver tumor resection were investigated. Nine to 10 liver biopsies at least 5 mm apart were taken from each of 12 removed human livers using Trucut needles. Hydroxyproline level of each liver core was determined. Sections>1 cm2 and stained by Sirius red were used for the reference staging of liver fibrosis in each patient according to the METAVIR scoring system.Hydroxyproline levels for the three groups, F0-1, F2-3, and F4, were significantly elevated as the fibrosis score increased. There was a wide range of hydroxyproline contents for the 9–10 biopsy samples from each liver, the coefficient of variation being between 13% and 36% (mean, 23%). Several differences were noted between the amount of collagen present according to hydroxyproline measurement and the stages of fibrosis according to histology.Although increases in collagen content (by hydroxyproline) approximately paralleled increases in fibrosis stage (by histology), there was considerable overlap and some discrepancies. Much work remains to be done to clarify the significance of the apparent huge variations in fibrosis within diseased livers. It is advisable for clinicians to interpret staging diagnoses by histological staging with some caution. [ABSTRACT FROM AUTHOR]

Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model.Rats were treated with rolipram (0.5–5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred.Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-α, IL-1β and GRO/CINC-1 levels. Rolipram, at doses of 0.5–5 mg/kg, suppressed serum transaminase and TNF-α production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg.In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production. [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PBC) has been reported in up to 4–6% of first degree relatives of patients with the disease. In addition, immune abnormalities, including hypergammaglobulinemia, autoantibodies and increased frequency of autoimmune disorders, were reported in family members of PBC patients. The aim of the present study was to investigate the prevalence of PBC in relatives of patients with PBC, and to investigate the occurrence of chronic liver disease (CLD) and immune abnormalities in these subjects. One-hundred first degree relatives of 26 patients with PBC were interviewed and submitted to physical examination and determination of liver enzymes, γ-globulin, bilirubin and auto-antibodies, including antinuclear (ANA), antismooth muscle (SMA), antimitochondrial antibodies (AMA) by indirect immunofluorescence (IIF) and anti-M2 antibody by immunoblotting (IB). Immune disturbances were rarely observed in relatives of PBC patients. Higher γ-globulin levels, SMA and ANA were detected in four, eight and two family members, respectively. In most subjects, these autoantibodies were either in low titers or associated with concurrent diseases. Only four relatives had extrahepatic autoimmune diseases and another eight exhibited other CLD. Primary biliary cirrhosis was detected in a sister of one patient. Additionally, two other relatives of PBC patients who tested negative for AMA by IIF showed reactivity for anti-M2 by IB. Immune disturbances, including ANA and SMA, are uncommon in family members of PBC patients. Conversely, anti-M2 antibodies and overt PBC do occur in relatives of PBC patients, even in Brazil where the disease is quite rare. [ABSTRACT FROM AUTHOR]

Alcoholic hepatitis is a potentially life-threatening complication of alcoholic abuse, typically presenting with symptoms and signs of hepatitis in the presence of an alcohol use disorder. The definitive diagnosis requires liver biopsy, but this is not generally required. The pathogenesis is uncertain, but relevant factors include metabolism of alcohol to toxic products, oxidant stress, acetaldehyde adducts, the action of endotoxin on Kupffer cells, and impaired hepatic regeneration. Mild alcoholic hepatitis recovers with abstinence and the long-term prognosis is determined by the underlying disorder of alcohol use. Severe alcoholic hepatitis is recognized by a Maddrey discriminant function >32 and is associated with a short-term mortality rate of almost 50%. Primary therapy is abstinence from alcohol and supportive care. Corticosteroids have been shown to be beneficial in a subset of severely ill patients with concomitant hepatic encephalopathy, but their use remains controversial. Pentoxifylline has been shown in one study to improve short-term survival rates. Other pharmacological interventions, including colchicine, propylthiouracil, calcium channel antagonists, and insulin with glucagon infusions, have not been proven to be beneficial. Nutritional supplementation with available high-calorie, high-protein diets is beneficial, but does not improve mortality. Orthotopic liver transplantation is not indicated for patients presenting with alcoholic hepatitis who have been drinking until the time of admission, but may be considered in those who achieve stable abstinence if liver function fails to recover. [ABSTRACT FROM AUTHOR]

Abstract Background: Heat-shock proteins (HSP) play an essential role in the sequestration and reparation of denatured cellular proteins. Because ethanol treatment can result in oxidative stress-induced protein damage, it is possible that expression of HSP is altered after ethanol consumption. Dose–response and time-course studies were performed to investigate whether acute and chronic intragastric ethanol administration can induce tissue damage, oxidative stress and expression of the heat-shock proteins HSP60 and HSP72 in the pancreas and liver of male Wistar rats. Methods: Laboratory and morphological analysis of pancreatic and liver damage were investigated. The degree of oxidative stress was assessed by measurement of the reduced glutathione content, lipid peroxidation and protein oxidation. The levels of HSP were examined by western blot analysis. Results: Ethanol administration dose- and time-dependently elevated the serum ethanol concentration and hepatic enzyme activities. Chronic ethanol treatment also resulted in morphological damage of the liver. We observed that acute and chronic ethanol consumption had markedly different effects on the oxidative parameters in the pancreas and liver. Acute ethanol administration caused oxidative stress in the liver, whereas there was no such effect in the pancreas. In contrast, chronic ethanol feeding resulted in oxidative stress in both the pancreas and the liver. Furthermore, neither acute nor chronic ethanol intake induced the synthesis of HSP, a major defense system against cellular damage in the examined organs. Conclusion: Ethanol administration generates oxidative stress in the pancreas and liver, but fails to induce HSP in rats. © 2003 Blackwell Publishing Asia Pty Ltd. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims: Hepatocellular carcinoma (HCC) is a common killer cancer in the world. Recently, abnormal activation of the Wnt pathway has been found to be involved in the carcinogenesis of several human cancers including HCC. The goal of the present study was to investigate the mechanism of inappropriate activation of the Wnt pathway in hepatocarcinogenesis. Methods: We analyzed the alterations of three key components of the Wnt pathway: β-catenin, glycogen synthase kinase (GSK)-3β and T-cell factor (Tcf)-4 in 34 HCC and paracancerous normal liver by immunohistochemistry, polymerase chain reaction (PCR)–single-strand conformation polymorphism (SSCP), direct sequencing, and quantitative real-time reverse transcription (RT)–PCR. Results: We found that 61.8% (21/34) of all HCC examined showed an abnormal β-catenin protein accumulation in the cytoplasm or nuclei. The RT–PCR–SSCP and direct sequencing showed that β-catenin exon 3 mutations existed in 44.1% (15/34) of the HCC. No mutations of GSK-3β or Tcf-4 were detected in HCC. Moreover, messenger RNA of β-catenin and Tcf-4, but not GSK-3β, was found to be overexpressed in HCC. On analyzing the relationship between alterations of β-catenin or Tcf-4 and C-myc or Cyclin D1 expression, we found that mutations of β-catenin, as well as overexpression of β-catenin or the Tcf-4 gene were independently correlated with C-myc gene overexpression in HCC. Conclusion: Our present findings strongly suggest that mutations of β-catenin, as well as overexpression of β-catenin and the Tcf-4 gene, independently activate the Wnt pathway in HCC, with the target gene most likely to be C-myc . [ABSTRACT FROM AUTHOR]

Abstract In experimental models, which induce liver damage and simultaneously block hepatocyte proliferation, the recruitment of a hepatic progenitor cell population comprised of oval cells is invariably observed. There is a substantial body of evidence to suggest that oval cells are involved in liver regeneration, as they differentiate into hepatocytes and biliary cells. Recently, bone marrow cells were shown to be a source of a stem cells with the capacity to repopulate the liver. Presently, the relationship between bone marrow cells and oval cells is unclear. Investigations will be greatly assisted by the availability of in vitro models based on a knowledge of cytokines that affect oval cells. While the cytokines, which regulate the different hematopoietic lineages, are well characterized, there is relatively little information regarding those that influence oval cells. This review outlines recent developments in the field of oval cell research and focuses on cytokines and growth factors that have been implicated in regulating oval cell proliferation and differentiation. © 2003 Blackwell Publishing Asia Pty Ltd. [ABSTRACT FROM AUTHOR]

Abstract Reactive oxygen species (ROS) are important cytotoxic and signalling mediators in the pathophysiology of inflammatory liver diseases. They can be generated by resident and infiltrating phagocytes and/or intracellularly in every liver cell type after stimulation with cytokines. Although ROS are able to cause cell destruction by massive lipid peroxidation, in most cases, ROS are more likely to modulate signal transduction pathways by affecting redox-sensitive enzymes, organelles (e.g. mitochondria) and transcription factors. Thus, ROS can directly induce and/or regulate apoptotic and necrotic cell death. In addition, ROS can have indirect effects on the pathophysiology by supporting protease activity through inactivation of antiproteases and by modulating the formation of inflammatory mediators and adhesion molecules. Many of the effects of ROS may occur simultaneously or sequentially in the pathophysiology. Although mainly described in this review as detrimental, ROS are essential for host-defence functions of phagocytes and can modulate the formation of mediators involved in regulating sinusoidal blood flow and liver regeneration. Thus, continuous efforts are necessary to improve our understanding of the role of ROS in the pathophysiology of inflammatory liver diseases and to discover therapeutic interventions that selectively target the negative effects of reactive oxygen formation. [ABSTRACT FROM AUTHOR]

Abstract The participation of matrix metalloproteinases (MMP) and their specific inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMP), in both the formation and degradative recovery processes of liver fibrosis were mainly reviewed from the molecular biological aspect. Since authors first reported increased activity of interstitial collagenase in the early stage of hepatic fibrosis in rats induced by chronic CCl4 intoxication, in baboons fed alcohol chronically and in patients with alcoholic fibrosis, other investigators have also demonstrated increased activity biologically and histochemically. However, species-specific differences in response have been found and gene-level research on the rat model has not demonstrated increased mRNA transcription of collagenase. It has also been clarified that activated stellate cells can also produce matrix components. Very recently, authors observed the participation of interstitial collagenase in the recovery from experimental hepatic fibrosis by using polymerase chain reaction northern blotting and in situ hybridization. The in situ hybridization findings not only demonstrated the cells responsible for interstitial collagenase, but also suggested a great deal about the mechanism of recovery from fibrosis. Hepatic stellate cells are activated via the expression of c-myb and nuclear factor-κB (NFκB) which is induced by oxidative stress, and inhibited by antioxidant (1-α-tocopherol) and butylated hydroxytoluene. The activation mechanism is now being revealed. The relationship between the activation mechanism of stellate cells and the production and secretion of MMP and TIMP in the formation and recovery process of hepatic fibrosis should be investigated from the promoter gene level. This approach might help develop a new strategy for the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Editorial. Explains the exhibition by the anti-ulcer drug lafutidine of an antisecretory effect via a histamine H[sub 2] receptor blockade and a gastroprotective activity against several necrotizing agents. Ability of the drug to increase hepatic blood flow; Speculation that liver sinusoid dilatation is the most likely mechanism underlying the central thyrotropin-releasing hormone-induced stimulation of hepatic blood flow.