Comparative Hepatology - Most accessed articles

Serum levels of soluble Fas, soluble tumor necrosis factor-receptor II, interleukin-2 receptor and interleukin-8 as early predictors of hepatocellular carcinoma in Egyptian patients with hepatitis C virus genotype-4

Abdel-Rahman Zekri — 2010-01-05T00:00:00Z

Background: Liver disease progression from chronic hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) is associated with an imbalance between T-helper 1 and T-helper 2 cytokines. Evaluation of cytokines as possible candidate biomarkers for prediction of HCC was performed using soluble Fas (sFas), soluble tumor necrosis factor receptor-II (sTNFR-II), interleukin-2 receptor (IL-2R) and interleukin-8 (IL-8). Results: The following patients were recruited: 79 with HCV infection, 30 with HCC, 32 with chronic liver disease associated with elevated liver enzyme levels (with or without cirrhosis) in addition to 17 with chronic HCV with persistent normal alanine aminotransferase levels (PNALT). Nine normal persons negative either for HCV or for hepatitis B virus were included as a control group. All persons were tested for sFas, sTNFR-II, IL-2R and IL-8 in their serum by quantitative ELISA. HCC patients had higher levels of liver enzymes but lower log-HCV titer when compared to the other groups. HCC patients had also significantly higher levels of sFas, sTNFR-II and IL-2R and significantly lower levels of IL-8 when compared to the other groups. Exclusion of HCC among patients having PNALT could be predicted with 90% sensitivity and 70.6% specificity when sTNFR-II is ≥ 389 pg/ml or IL-8 is < 290 pg/ml. Conclusions: Serum TNFR-II, IL-2Rα and IL-8, may be used as combined markers in HCV-infected cases for patients at high risk of developing HCC; further studies, however, are mandatory to check these findings before their application at the population level.

Daytime food restriction alters liver glycogen, triacylglycerols, and cell size: a histochemical, morphometric, and ultrastructural study

Mauricio Diaz-Munoz — 2010-02-23T00:00:00Z

Background: Temporal restriction of food availability entrains circadian behavioral and physiological rhythms in mammals by resetting peripheral oscillators. This entrainment underlies the activity of a timing system, different from the suprachiasmatic nuclei (SCN), known as the food entrainable oscillator (FEO). So far, the precise anatomical location of the FEO is unknown. The expression of this oscillator is associated with an enhanced arousal prior to the food presentation that is called food anticipatory activity (FAA). We have focused on the study of the role played by the liver as a probable component of the FEO. The aim of this work was to identify metabolic and structural adaptations in the liver during the expression of the FEO, as revealed by histochemical assessment of hepatic glycogen and triacylglycerol contents, morphometry, and ultrastructure in rats under restricted feeding schedules (RFS). Results: RFS promoted a decrease in the liver/body weight ratio prior to food access, a reduction of hepatic water content, an increase in cross-sectional area of the hepatocytes, a moderate reduction in glycogen content, and a striking decrease in triacylglyceride levels. Although these adaptation effects were also observed when the animal displayed FAA, they were reversed upon feeding. Mitochondria observed by electron microscopy showed a notorious opacity in the hepatocytes from rats during FAA (11:00 h). Twenty four hour fasting rats did not show any of the modifications observed in the animals expressing the FEO. Conclusions: Our results demonstrate that FEO expression is associated with modified liver handling of glycogen and triacylglycerides accompanied by morphometric and ultrastructural adaptations in the hepatocytes. Because the cellular changes detected in the liver cannot be attributed to a simple alternation between feeding and fasting conditions, they also strengthen the notion that RFS promotes a rheostatic adjustment in liver physiology during FEO expression.

Keratin 19 marks poor differentiation and a more aggressive behaviour in canine and human hepatocellular tumours

Renee van Sprundel — 2010-02-18T00:00:00Z

Background: The expression of Keratin 19 (K19) was reported in a subset of hepatocellular carcinomas (HCCs). K19 positive HCCs are associated with an increased malignancy compared to K19 negative HCCs. No suitable mouse models exist for this subtype of HCC, nor is the incidence of K19 expression in hepatocellular neoplasia in model animals known. Therefore, we compared the occurrence and tumour behaviour of K19 positive hepatocellular neoplasias in dog and man. Results: The expression of hepatocellular differentiation (HepPar-1), biliary/progenitor cell (K7, K19), and malignancy (glypican-3) markers was semi-quantitatively assessed by immunohistochemistry. The histological grade of tumour differentiation was determined according to a modified classification of Edmondson and Steiner; the staging included intrahepatic, lymph node or distant metastases. Four of the 34 canine hepatocellular neoplasias showed K19 positivity (12%), of which two co-expressed K7. K19 positive tumours did not express HepPar-1, despite the histological evidence of a hepatocellular origin. Like in human HCC, all K19 positive hepatocellular neoplasias were glypican-3 positive and histologically poorly differentiated and revealed intra- or extrahepatic metastases whereas K19 negative hepatocellular neoplasias did not. Conclusions: K19 positive hepatocellular neoplasias are highly comparable to man and occur in 12% of canine hepatocellular tumours and are associated with a poorly differentiated histology and aggressive tumour behaviour.

Eggshell and egg yolk proteins in fish: hepatic proteins for the next generation: oogenetic, population, and evolutionary implications of endocrine disruption

Augustine Arukwe — 2003-03-06T00:00:00Z

The oocyte is the starting point for a new generation. Most of the machinery for DNA and protein synthesis needed for the developing embryo is made autonomously by the fertilized oocyte. However, in fish and in many other oviparous vertebrates, the major constituents of the egg, i.e. yolk and eggshell proteins, are synthesized in the liver and transported to the oocyte for uptake. Vitellogenesis, the process of yolk protein (vitellogenin) synthesis, transport, and uptake into the oocyte, and zonagenesis, the synthesis of eggshell zona radiata proteins, their transport and deposition by the maturing oocyte, are important aspects of oogenesis. The many molecular events involved in these processes require tight, coordinated regulation that is under strict endocrine control, with the female sex steroid hormone estradiol-17β in a central role. The ability of many synthetic chemical compounds to mimic this estrogen can lead to unscheduled hepatic synthesis of vitellogenin and zona radiata proteins, with potentially detrimental effects to the adult, the egg, the developing embryo and, hence, to the recruitment to the fish population. This has led to the development of specific and sensitive assays for these proteins in fish, and the application of vitellogenin and zona radiata proteins as informative biomarkers for endocrine disrupting effects of chemicals and effluents using fish as test organisms. The genes encoding these important reproductive proteins are conserved in the animal kingdom and are products of several hundred million years of evolution.

Chlamydia trachomatis growth inhibition and restoration of LDL-receptor level in HepG2 cells treated with mevastatin

Yuriy Bashmakov — 2010-01-28T00:00:00Z

Background: Perihepatitis is rare but consistently occurring extragenital manifestation of untreated Chlamydia trachomatis infection. Despite of possible liver involvement in generalized C. trachomatis infection, the ability of the pathogen to propagate in the hepatic cells and its impact on liver functions is not thoroughly investigated. The effect of mevastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, on C. trachomatis growth in human hepatoma cell line HepG2 has been studied. Bacterial growth was assessed by immunostaining with FITC-labeled monoclonal antibody against chlamydial lipopolysaccharide and by RT-PCR for two chlamydial genetic markers (16S rRNA and euo). Results: Chlamydial inclusion bodies were seen in approximately 50% of hepatocytes at 48 hours in the post infection period. Lysates obtained from infected hepatocytes were positive in the infective progeny test at 48 and especially in 72 hours after infection initiation. It has been shown that chlamydial infection in hepatocytes also leads to the decline of LDL-receptor mRNA which reflects infection multiplicity rate. Additions of mevastatin (1, 20 and 40 μM) 1 hour before inoculation restored and upregulated LDL-receptor mRNA level in a dose-dependent manner. Mevastatin treatment had no effect on internalization of chlamydial particles. However it reduced drastically the number of chlamydial 16S rRNA and euo transcripts as well as overall infection rate in HepG-2 cells. Complete eradication of infection has been seen by immunofluorescent staining at 40 μM mevastatin concentration, when expression level of chlamydial 16S rRNA and euo was undetectable. Lower concentration of mevastatin (20 μM) promoted euo expression level and the appearance of atypically small chlamydial inclusions, while there was a noticeable reduction in the number of infected cells and 16S rRNA transcripts. Conclusions: C. trachomatis can efficiently propagate in hepatocytes affecting transcription rate of some liver-specific genes. Ongoing cholesterol synthesis is essential for chlamydial growth in hepatocytes. Inhibitors of cholesterol biosynthesis can supplement conventional strategy in the management of C. trachomatis infection.

Increased sinusoidal flow is not the primary stimulus to liver regeneration

Kim Mortensen — 2010-01-20T00:00:00Z

Background: Hemodynamic changes in the liver remnant following partial hepatectomy (PHx) have been suggested to be a primary stimulus in triggering liver regeneration. We hypothesized that it is the increased sinusoidal flow per se and hence the shear-stress stimulus on the endothelial surface within the liver remnant which is the main stimulus to regeneration. In order to test this hypothesis we wanted to increase the sinusoidal flow without performing a concomitant liver resection. Accordingly, we constructed an aorto-portal shunt to the left portal vein branch creating a standardized four-fold increase in flow to segments II, III and IV. The impact of this manipulation was studied in both an acute model (6 animals, 9 hours) using a global porcine cDNA microarray chip and in a chronic model observing weight and histological changes (7 animals, 3 weeks). Results: Gene expression profiling from the shunted segments does not suggest that increased sinusoidal flow per se results in activation of genes promoting mitosis. Hyperperfusion over three weeks results in the whole liver gaining a supranormal weight of 3.9% of the total body weight (versus the normal 2.5%). Contrary to our hypothesis, the weight gain was observed on the non-shunted side without an increase in sinusoidal flow. Conclusions: An isolated increase in sinusoidal flow does not have the same genetic, microscopic or macroscopic impact on the liver as that seen in the liver remnant after partial hepatectomy, indicating that increased sinusoidal flow may not be a sufficient stimulus in itself for the initiation of liver regeneration.

FNH-like nodules: Possible precursor lesions in patients with focal nodular hyperplasia (FNH)

Sebastien Lepreux — 2003-06-26T00:00:00Z

Background: The typical lesion of focal nodular hyperplasia (FNH) is a benign tumor-like mass characterized by hepatocytic nodules separated by fibrous bands. The solitary central artery with high flow and the absent portal vein give the lesions their characteristic radiological appearance. The great majority of cases seen in daily practice conform to the above description. Additional small nodules (from 1-2 up to 15-20 mm in diameter) detected by imaging techniques or on macroscopic examination may be difficult to identify as representing FNH if they lack the key features of FNH as defined in larger lesions. The aim of this study was to characterize these small nodules, and to compare their characteristics with those of typical lesions of FNH present in the same specimens. Results: Eight patients underwent hepatic resections for the removal of a mass lesion ("nodule") diagnosed as: FNH (1 patient); nodules of unknown nature (5 patients); or nodules thought to be adenoma or hepatocellular carcinoma (2 patients). Six nodules out of 9 discovered by imaging techniques met histopathological criteria for the diagnosis of typical FNH, at least in parts of the nodule; 2 nodules corresponded to a minor form of FNH ("subtle FNH") and one nodule to a steatotic area. Although FNH was thought to be found in a normal or nearly normal liver, this study revealed that, in addition, there were various types of small FNH-like nodules and vascular abnormalities in the liver with typical FNH nodule. The various types of small FNH-like nodules (n = 8, diameter 2 to 20 mm) consisted of the association to various degrees of numerous and/or enlarged arteries in portal tracts or in septa, with hyperplastic foci, slight ductular reaction, and regions of sinusoidal dilatation, accompanied by thin fibrous bands. Vascular abnormalities consisted of unpaired arteries, portal tracts with arteries larger than the associated bile duct, and regions of sinusoidal dilatation. Conclusions: Although these small nodules can be considered as insufficient type or abortive forms of FNH, or adenoma, they can be precursors of the large mass lesions in which FNH was recognized and defined.

Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options

Olav Gressner — 2007-07-30T00:00:00Z

Despite intensive studies, the clinical opportunities for patients with fibrosing liver diseases have not improved. This will be changed by increasing knowledge of new pathogenetic mechanisms, which complement the "canonical principle" of fibrogenesis. The latter is based on the activation of hepatic stellate cells and their transdifferentiation to myofibroblasts induced by hepatocellular injury and consecutive inflammatory mediators such as TGF-β. Stellate cells express a broad spectrum of matrix components. New mechanisms indicate that the heterogeneous pool of (myo-)fibroblasts can be supplemented by epithelial-mesenchymal transition (EMT) from cholangiocytes and potentially also from hepatocytes to fibroblasts, by influx of bone marrow-derived fibrocytes in the damaged liver tissue and by differentiation of a subgroup of monocytes to fibroblasts after homing in the damaged tissue. These processes are regulated by the cytokines TGF-β and BMP-7, chemokines, colony-stimulating factors, metalloproteinases and numerous trapping proteins. They offer innovative diagnostic and therapeutic options. As an example, modulation of TGF-β/BMP-7 ratio changes the rate of EMT, and so the simultaneous determination of these parameters and of connective tissue growth factor (CTGF) in serum might provide information on fibrogenic activity. The extension of pathogenetic concepts of fibrosis will provide new therapeutic possibilities of interference with the fibrogenic mechanism in liver and other organs.

Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review

Filip Braet — 2002-08-23T00:00:00Z

This review provides a detailed overview of the current state of knowledge about the ultrastructure and dynamics of liver sinusoidal endothelial fenestrae. Various aspects of liver sinusoidal endothelial fenestrae regarding their structure, origin, species specificity, dynamics and formation will be explored. In addition, the role of liver sinusoidal endothelial fenestrae in relation to lipoprotein metabolism, fibrosis and cancer will be approached.

Animal models of copper-associated liver disease

I Carmen Fuentealba — 2003-04-03T00:00:00Z

Recent advances in molecular biology have made possible the identification of genetic defects responsible for Wilson's disease, Indian childhood cirrhosis and copper toxicosis in Long Evans Cinnamon rats, toxic milk mice, and Bedlington terriers. The Wilson's disease gene is localized on human chromosome 13 and codes for ATP7B, a copper transporting P-type ATPase. A genetic defect similar to that of Wilson's disease occurs in Long Evans Cinnamon rats and toxic milk mice. Familial copper storage disorders in Bedlington and West Highland white terriers are associated with early subclinical disease, and copper accumulation with subsequent liver injury culminating in cirrhosis. The canine copper toxicosis locus in Bedlington terriers has been mapped to canine chromosome region CFA 10q26. Recently, a mutated MURR1 gene was discovered in Bedlington terriers affected with the disease. Idiopathic childhood cirrhosis is biochemically similar to copper toxicosis in Bedlington terriers, but clinically much more severe. Both conditions are characterized by the absence of neurologic damage and Kayser-Fleisher rings, and normal ceruloplasmin levels. A recent study added North Ronaldsay sheep to the list of promising animal models to study Indian childhood cirrhosis. Morphologic similarities between the two conditions include periportal to panlobular copper retention and liver changes varying from active hepatitis to panlobular pericellular fibrosis, and cirrhosis. Certain copper-associated disorders, such as chronic active hepatitis in Doberman pinschers and Skye terrier hepatitis are characterized by copper retention secondary to the underlying disease, thus resembling primary biliary cirrhosis in humans. Copper-associated liver disease has increasingly being recognized in Dalmatians. Copper-associated liver diseases in Dalmatians and Long Evans Cinnamom rats share many morphologic features. Fulminant hepatic failure in Dalmatians is characterized by high serum activities of alanine aminotransferase and aspartate aminotransferase, and severe necrosis of centrilobular areas (periacinar, zone 3) hepatocytes. Macrophages and surviving hepatocytes contain copper-positive material. Liver disease associated with periacinar copper accumulation has also been described in Siamese cats. Many questions regarding copper metabolism in mammals, genetic background, pathogenesis and treatment of copper-associated liver diseases remain to be answered. This review describes the similarities between the clinico-pathological features of spontaneous copper-associated diseases in humans and domestic animals.