ISRN hepatology最新文献

Hepatitis C virus (HCV) is an important causative agent of liver disease, but factors that determine the resolution or progression of infection are poorly understood. In this study, we suggested that existence of immunosuppressive mechanisms, supported by regulatory T cells and especially the regulatory T cell 1 subset (Tr1), may explain the impaired immune response during infection and thus the fibrosis aggravation to hepatocellular carcinoma (HCC). Using quantitative real-time PCR, we investigated the intra-hepatic presence of Tr1 cells in biopsies from a genotype 1b infected patient followed for an 18-year period from cirrhosis to HCC. We described a significant increase of gene expression in particular for the cytokines IL-10, TGF-β, and their receptors that were perfectly correlated with an increased expression of the Tr1 specific markers (combined expression of CD4, CD18, and CD49b). This was strongly marked since the patient evolved in the pathology and could explain the failure of the treatment. In conclusion, evidence of regulatory T cell installation in the liver of chronically infected patient with cirrhosis and HCC suggests for the first time a key role for these cells in the course of HCV infection.

The increase in the number of people with obesity- and noninsulin-dependent diabetes mellitus has become a major public health concern. Insulin resistance is a common feature closely associated with human obesity and diabetes. Insulin regulates metabolism, at least in part, via the control of the expression of the hepatic genes involved in glucose and fatty acid metabolism. Insulin resistance is always associated with profound changes of the expression of hepatic genes for glucose and lipid metabolism. As an essential micronutrient, vitamin A (VA) is needed in a variety of physiological functions. The active metablite of VA, retinoic acid (RA), regulates the expression of genes through the activation of transcription factors bound to the RA-responsive elements in the promoters of RA-targeted genes. Recently, retinoids have been proposed to play roles in glucose and lipid metabolism and energy homeostasis. This paper summarizes the recent progresses in our understanding of VA metabolism in the liver and of the potential transcription factors mediating RA responses. These transcription factors are the retinoic acid receptor, the retinoid X receptor, the hepatocyte nuclear factor 4α, the chicken ovalbumin upstream promoter-transcription factor II, and the peroxisome proliferator-activated receptor β/δ. This paper also summarizes the effects of VA status and RA treatments on the glucose and lipid metabolism in vivo and the effects of retinoid treatments on the expression of insulin-regulated genes involved in the glucose and fatty acid metabolism in the primary hepatocytes. I discuss the roles of RA production in the development of insulin resistance in hepatocytes and proposes a mechanism by which RA production may contribute to hepatic insulin resistance. Given the large amount of information and progresses regarding the physiological functions of VA, this paper mainly focuses on the findings in the liver and hepatocytes and only mentions the relative findings in other tissues and cells.

Background. N-terminal probrain natriuretic peptide (NT-proBNP) is a hormone involved in the regulation of cardiovascular homeostasis. Changes in serum NT-proBNP during large volume paracentesis (LVP) in patients with ascites have never before been examined. Aims. To determine if significant changes in serum NT-proBNP occur in patients undergoing LVP and the associated clinical correlates in patients with cirrhosis. Method. A total of 45 patients with ascites were prospectively recruited. Serum NT-proBNP, biochemistry, and haemodynamics were determined at baseline and at key time points during and after paracentesis. Results. 34 patients were analysed; 19 had ascites due to cirrhosis and 15 from malignancy. In those with cirrhosis, NT-proBNP decreased by 77.3 pg/mL at 2 L of drainage and 94.3 pg/mL at the end of paracentesis, compared with an increase of 10.5 pg/mL and 77.2 pg/mL in cancer patients at the same time points (P = 0.05 and P = 0.03). Only congestive cardiac failure (CCF) was an independent predictor of significant NT-proBNP changes at the end of drainage in cirrhotic patients (P < 0.01). There were no significant changes in haemodynamics or renal biochemistry for either group. Conclusion. Significant reductions in serum NT-proBNP during LVP occur in patients with cirrhosis but not malignancy, and only comorbid CCF appeared to predict such changes.

Interleukin-10 (IL-10) and interleukin-6 (IL-6) have been reported to be related to hepatocellular carcinoma (HCC) prognosis. This study aimed to investigate the clinical usefulness of serum levels of IL-6 and IL-10 as biomarkers for HCC among high-risk patients. Materials and Methods. 80 individuals were enrolled in this study; they were categorized into 4 groups: group 1 healthy individuals (NC) (n = 20), group 2 chronic hepatitis C virus (HCV) patients (n = 20), group 3 cirrhotic patients (LC) (n = 20), and HCC group (n = 20). Using ELISA technique serum levels of IL-6, IL-10, and alpha fetoprotein (AFP) were evaluated in all groups. Results. The mean serum levels of IL-6 were significantly higher in HCC than in LC, HCV, and NC groups (13.99 ± 1.80, 7.49 ± 0.43, 5.78 ± 0.74, and 2.57 ± 0.31), respectively (P < 0.05); also the serum levels of IL-10 were significantly higher in HCC compared with LC, HCV, and NC groups (13.69 ± 1.89, 7.37 ± 0.53, 5.18 ± 0.6, and 3.31 ± 0.42) (P < 0.05). We also found that the tumor size is correlated strongly with IL-6 and IL-10 levels (r = 0.925, P < 0.001; r = 0.821, P < 0.001), respectively. Conclusion. The combination of those markers may help to identify a group of HCC patients with low AFP.

Introduction. The aim of this study was to assess whether hepatitis B virus drug resistant mutations antedated the widespread use of nucleos(t)ide analogues in treatment naïve patients. A number of reports have suggested that drug resistant mutants can be detected in apparently treatment naïve patients. Study. Fifty deidentified serum samples collected from 1986 to 1992 from patients with replicative chronic HBV infection at the University of Miami were genotyped and tested for resistance mutations using a line probe assay InnoLiPA HBV DR v2/v3. Serum HBV DNA was measured. All patients had documented chronic HBV infection with a detectable viral load, HBeAg seropositivity, and absence of HIV infection. Results. Of the 50 individuals included, 86% were male, mean age was 40 ± 12 years, and mostly genotype A. The mean HBV DNA was 126 pg/mL (range 6.4 to 557.0). No mutations were identified. Conclusions. The absence of drug induced mutations in these sera collected several years prior to the introduction of oral antiviral therapy suggests that these mutations do not occur in treatment naïve populations. Detection of drug resistance in an apparently treatment naïve subject suggests either unrecognized prior antiviral therapy or infection by an inoculum from a treatment experienced patient.

Background. Gastrinomas are rare functional neuroendocrine tumors causing the Zollinger-Ellison syndrome (ZES). At presentation, up to 25% of gastrinomas are metastasized, predominantly to the liver. Embolization of liver metastases might reduce symptoms of ZES although a postembolization syndrome can occur. In this study, the results of embolization are presented, and the literature results are described. Methods. From a prospective database of pancreatic neuroendocrine tumors, all patients with liver metastatic gastrinomas were selected if treated with arterial embolization. Primary outcome parameters were symptom reduction, complications, and response rate. The literature search was performed with these items. Results. Three patients were identified; two presented with synchronous liver metastases. All the three patients had symptoms of ZES before embolization. Postembolization syndrome occurred in two patients. Six months after embolization, all the 3 patients had a clinical and complete radiological response; a biochemical response was seen in 2/3 patients. From the literature, only a small number of gastrinoma patients treated with liver embolization for liver metastases were found, and similar results were described. Conclusion. Selective liver embolization is an effective and safe therapy for the treatment of liver metastatic gastrinomas in the reduction of ZES. Individual treatment strategies must be made for the optimal success rate.

Gastrointestinal bleeding related to portal hypertension is a serious complication in patients with liver cirrhosis. Most patients bleed from esophageal or gastric varices, but bleeding from ectopic varices or portal hypertensive gastropathy is also possible. The management of acute bleeding has changed over the last years. Patients are managed with a combination of endoscopic and pharmacologic treatment. The endoscopic treatment of choice for esophageal variceal bleeding is variceal band ligation. Bleeding from gastric varices is treated by injection with cyanoacrylate. Treatment with vasoactive drugs as well as antibiotic treatment is started before or at the time point of endoscopy. The first-line treatment for primary prophylaxis of esophageal variceal bleeding is nonselective beta blockers. Pharmacologic therapy is recommended for most patients; band ligation is an alternative in patients with contraindications for or intolerability of beta blockers. Treatment options for secondary prophylaxis include variceal band ligation, beta blockers, a combination of nitrates and beta blockers, and combination of band ligation and pharmacologic treatment. A clear superiority of one treatment over the other has not been shown. Bleeding from portal hypertensive gastropathy or ectopic varices is less common. Treatment options include beta blocker therapy, injection therapy, and interventional radiology.

Arsenic is a Group I human carcinogen, and chronic arsenic exposure through drinking water is a major threat to human population. Liver is one of the major organs for the detoxification of arsenic. The present study was carried out in mice in vivo after arsenic treatment through drinking water at different doses and time of exposure. Arsenic toxicity is found to be mediated by reactive oxygen species. Nuclear factor (erythroid-2 related) factor 2 (Nrf2)/Keap1 (Kelch-like ECH-associated protein 1)/ARE (antioxidant response element)-driven target gene system protects cells against oxidative stress and maintains cellular oxidative homeostasis. Our result showed 0.4 ppm, 2 ppm, and 4 ppm arsenic trioxide treatment through drinking water for 30 days and 90 days induced damages in the liver of Swiss albino mice as evidenced by histopathology, disturbances in liver function, induction of heat shock protein 70, modulation of trace elements, alteration in reduced glutathione level, glutathione-s-transferase and catalase activity, malondialdehyde production, and induction of apoptosis. Cellular Nrf2 protein level and mRNA level increased in all treatment groups. Keap1 protein as well as mRNA level decreased concomitantly in arsenic treated mice. Our study clearly indicates the important role of Nrf2 in activating ARE driven genes related to GSH metabolic pathway and also the adaptive response mechanisms in arsenic induced hepatotoxicity.

A recent analysis of Egypt's first nationally representative survey of hepatitis C virus (HCV) infection found female genital cutting (FGC) to be an independent risk factor for HCV infection for women in urban areas. We use the same dataset to extend this analysis. In an ecological analysis, we find a strong association between FGC and HCV prevalence (Pearson R (2)-74%;  P < 0.0001). HCV prevalence is significantly higher if FGC is performed by a non-Doctor (15.4%) than a Doctor (4.2%; P < 0.001), and the calculated population attributable fraction of FGC for prevalent HCV seropositivity is high in women (79.8%).

Metastases are largely responsible for cancer deaths in solid tumors due to the lack of effective therapies against disseminated disease, and there is an urgent need to fill this gap. This study demonstrates an orthotopic colorectal cancer (CRC) mouse model system to develop spontaneous metastasis in vivo and compare its reproducibility against human CRC. IGF1R-dependent GEO human CRC cells were used to study metastatic colonization using orthotopic transplantation procedures and demonstrated robust liver metastasis. Cell proliferation assays were performed both in the orthotopic primary colon and liver metastatic tumors, and human CRC patient's specimen and similar patterns in H&E and Ki67 staining were observed between the orthotopically generated primary and liver metastatic tumors and human CRC specimens. Microarray analysis was performed to generate gene signatures, compared with deposited human CRC gene expression data sets, analyzed by Oncomine, and revealed similarity in gene signatures with increased aggressive markers expression associated with CRC in orthotopically generated liver metastasis. Thus, we have developed an orthotopic mouse model that reproduces human CRC metastasis. This model system can be effective in developing new therapeutic strategies against disseminated disease and could be implemented for identifying genes that regulate the development and/or maintenance of established metastasis.