Future prospectives for the management of chronic hepatitis B

Chronic hepatitis B virus infection affects about 400 million people around the globe and causes approximately a million deaths a year. Since the discovery of interferon-α as a therapeutic option the treatment of hepatitis B has evolved fast and management has become increasingly complicated. The amount of viral replication reflected in the viral load （HBV-DNA） plays an important role in the development of cirrhosis and hepatocellular carcinoma. The current treatment modalities for chronic hepatitis B are immunomodulatory （interferons） and antiviral suppressants （nucleoside and nucleotide analogues） all with their own advantages and limitations. An overview of the treatment efficacy for both immunomodulatory as antiviral compounds is provided in order to provide the clinician insight into the factors influencing treatment outcome. With nucleoside or nucleotide analogues suppression of viral replication by 5-7 log10 is feasible, but not all patients respond to therapy. Known factors influencing treatment outcome are viral load, ALT levels and compliance. Many other factors which might influence treatment are scarcely investigated. Identifying the factors associated with response might result in stopping rules, so treatment could be adapted in an early stage to provide adequate treatment and avoid the development of resistance. The efficacy of compounds for the treatment of mutant virus and the cross-resistance is largely unknown. However, genotypic and phenotypic testing as well as small clinical trials provided some data on efficacy in this population. Discontinuation of nucleoside or nucleotide analogues frequently results in viral relapse; however, some patients have a sustained response. Data on the risk factors for relapse are necessary in order to determine when treatment can be discontinued safely. In conclusion： chronic hepatitis B has become a treatable disease; however, much research is needed to tailor therapy to an individual patient, to predict the sustainability of response and determine the best treatment for those failing treatment.

MicroRNAs, development of Barrett’s esophagus, and progression to esophageal adenocarcinoma

Barrett's esophagus is a premalignant condition caused by gastroesophageal reflux. Once developed, it can progress through varying grades of dysplasia to esoph-ageal adenocarcinoma. Whilst it is well accepted that Barrett's esophagus is caused by gastroesophageal reflux, the molecular mechanisms of its pathogenesis and progression to cancer remain unclear. MicroRNAs (miRNAs) are short segments of RNA that have been shown to control the expression of many human genes. They have been implicated in most cellular processes, and the role of miRNAs in disease development is be-coming increasingly evident. Understanding altered miRNA expression is likely to help unravel the molecular mechanisms that underpin the development of Barrett's esophagus and its progression to cancer.

A case of hepatic angiomyolipoma difficult to distinguish from hepatocellular carcinoma

We report a case of hepatic angiomyolipoma with uncommon clinical features. A 56-year-old man presented with a hepatic tumor in the caudate lobe. The tumor was hypoechoic on ultrasonography, showed early-phase hyperattenuation on enhanced computed tomography and did not absorb iron on superparamagnetic iron oxide-enhanced magnetic resonance imaging. Hepatocellular carcinoma was highly suspected, and the patient underwent hepatic resection. Histologically, the tumor was mainly composed of smooth muscle cells and contained small amounts of adipose cells and blood vessels. On immunohistochemical staining, the smooth muscle cells were positive for a melanocytic cell-specific monoclonal antibody. In cases with uncommon features of angiomyolipoma, it is quite difficult to distinguish angiomyolipoma from hepatocellular carcinoma.

Management of rectal foreign bodies: Description of a new technique and clinical practice guidelines

A number of techniques have been described to remove rectal foreign bodies. In this report, a novel endoscopic technique using a pneumatic dilatation balloon normally used in achalasia patients is presented. In addition, a systematic review of the literature was performed for non-operative methods to remove foreign bodies from the rectum. These results are summarised, presented as a practical at-a- glance overview and a flow chart is offered to guide the clinician in treatment decisions. The design of the flow chart was based on the aims to treat the patient preferably on an outpatient basis with minimally invasive techniques and if possible under conscious sedation rather than general anaesthesia.

Bone morphogenetic protein-2 is a negative regulator of hepatocyte proliferation downregulated in the regenerating liver

AIM: To characterize the expression and dynamic changes of bone morphogenetic protein (BMP)-2 in hepatocytes in the regenerating liver in rats after partial hepatectomy (PH), and examine the effects of BMP-2 on proliferation of human Huh7 hepatoma cells. METHODS: Fifty-four adult male Wistar rats were randomly divided into three groups: A normal control (NC) group, a partial hepatectomized (PH) group and a sham operated (SO) group. To study the effect of liver regeneration on BMP-2 expression, rats were sacrificed before and at different time points after PH or the sham intervention (6, 12, 24 and 48 h). For each time point, six rats were used in parallel. Expression and distribution of BMP-2 protein were determined in regenerating liver tissue by Western blot analysis and immunohistochemistry. Effects of BMP-2 on cell proliferation of human Huh7 hepatoma cell line were assessed using an MTT assay.RESULTS: In the normal liver strong BMP-2 expression was observed around the central and portal veins. The expression of BMP-2 decreased rapidly as measured by both immunohistochemistry and Western blot analysis. This decrease was at a maximum of 3.22 fold after 12 h and returned to normal levels at 48 h after PH. No significant changes in BMP-2 immunoreactivity were observed in the SO group. BMP-2 inhibited serum induced Huh7 cell proliferation.CONCLUSION: BMP-2 is expressed in normal adult rat liver and negatively regulates hepatocyte proliferation. The observed down regulation of BMP-2 following partial hepatectomy suggests that such down regulation may be necessary for hepatocyte proliferation.

Impact of bolus volume on small intestinal intra-luminal impedance in healthy subjects

AIM: To assess the impact of bolus volume on the characteristics of small intestinal (SI) impedance signals.METHODS: Concurrent SI manometry-impedance measurements were performed on 12 healthy volunteers to assess the pattern of proximal jejunal fluid bolus movement over a 14 cm-segment.Each subject was given 34 boluses of normal saline (volume from 1 to 30 mL) via the feeding tube placed immediately above the proximal margin of the studied segment.A bolus-induced impedance event occurred if there was > 12% impedance drop from baseline,over ≥ 3 consecutive segments within 10 s of bolus injection.A minor or major imped-ance event was defined as a duration of impedance drop < 60 s or ≥ 60 s,respectively.RESULTS: The minimum volume required for a detectable SI impedance event was 2 mL.A direct linear relationship between the SI bolus volume and the occurrence of impedance events was noted until SI bolus volume reached 10 mL,a volume which always produced an impedance flow event.There was a moderate correlation between the bolus volume and the duration of impedance drop (r = 0.63,P < 0.0001) and the number of propagated channels (r = 0.50,P < 0.0001).High volume boluses were associated with more major impedance events (≥ 10 mL boluses = 63%,3 mL boluses = 17%,and < 3 mL boluses = 0%,P = 0.02).CONCLUSION: Bolus volume had an impact on the type and length of propagation of SI impedance events and a threshold of 2 mL is required to produce an event.

Overlap syndromes among autoimmune liver diseases

The three major immune disorders of the liver are autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC) and primary sclerosing cholangitis(PSC).Variant forms of these diseases are generally called overlap syndromes,although there has been no standardised definition.Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.The AIH-PBC overlap syndrome is the most common form,affecting almost 10% of adults with AIH or PBC.Single cases of AIH and autoimmune cholangitis(AMA-negative PBC) overlap syndrome have also been reported.The AIH-PSC overlap syndrome is predominantly found in children,adolescents and young adults with AIH or PSC.Interestingly,transitions from one autoimmune to another have also been reported in a minority of patients,especially transitions from PBC to AIH-PBC overlap syndrome.Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment.Therapy for overlap syndromes is empiric,since controlled trials are not available in these rare disorders.Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes.In end-stage disease,liver transplantation is the treatment of choice.

Mesenteric panniculitis: Various presentations and treatment regimens

Mesenteric panniculitis is a rare, benign and chronic f ibrosing inflammatory disease that affects the adipose tissue of the mesentery of the small intestine and colon. The specific etiology of the disease is unknown. The diagnosis is suggested by computed tomography and is usually confirmed by surgical biopsies. Treatment is empirical and based on a few selected drugs. Surgical resection is sometimes attempted for def initive therapy, although the surgical approach is often limited. We report two cases of mesenteric panniculitis with two different presentations and subsequently varying treatment regimens. Adequate response was obtained in both patients. We present details of these cases as well as a literature review to compare various presentations, etiologies and potential treatment modalities.

Epigenetic changes in colorectal cancer

Epigenetic changes frequently occur in human colorectal cancer.Genomic global hypomethylation,gene promoter region hypermethylation,histone modifications,and alteration of miRNA patterns are major epigenetic changes in colorectal cancer.Loss of imprinting(LOI) is associated with colorectal neoplasia.Folate deficiency may cause colorectal carcinogenesis by inducing gene-specific hypermethylation and genomic global hypomethylation.HDAC inhibitors and demethylating agents have been approved by the FDA for myelodysplastic syndrome and leukemia treatment.Non-coding RNA is regarded as another kind of epigenetic marker in colorectal cancer.This review is mainly focused on DNA methylation,histone modification,and microRNA changes in colorectal cancer.

New therapeutic opportunities for Hepatitis C based on small RNA

Hepatitis C virus （HCV） infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, antisense oligonucleotides （ASO）, or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA （miR-222） in viral replication and discuss its potential for HCV molecular therapy.

Ileal lesions in patients with ulcerative colitis after ileo-rectal anastomosis:Relationship with colonic metaplasia

AIM:To assess whether in ulcerative colitis (UC) patients with ileo-rectal anastomosis (IRA), ileal lesions may develop in the neo-terminal-ileum and their possible relation with phenotypic changes towards colonic epithelium. METHODS: A total of 19 patients with IRA under regular follow up were enrolled, including 11 UC and 8 controls (6 Crohn’s disease, CD; 1 familial adenomatous polyposis, FAP; 1 colon cancer, colon K). Ileal lesions were identifi ed by ileoscopy with biopsies taken from the ileum (involved and uninvolved) and from the rectal stump. Staining included HE and immunohistochemistry using monoclonal antibodies against colonic epithelial protein CEP (Das-1) and human tropomyosin isoform 5, hTM5 (CG3). Possible relation between development of colonic metaplasia and ileal lesions was investigated.RESULTS: Stenosing adenocarcinoma of the rectal stump was detected in 1 UC patient. The neo-terminal ileum was therefore investigated in 10/11 UC patients. Ileal ulcers were detected in 7/10 UC, associated with colonic metaplasia in 4/7 (57.1%) and Das-1 and CG3 reactivity in 3/4 UC. In controls, recurrence occurred in 4/6 CD, associated with colonic metaplasia in 3/4 and reactivity with Das-1 and CG3 in 2/3. CONCLUSION: Present fi ndings suggest that in UC, ileal lesions associated with changes towards colonic epithelium may develop also after IRA. Changes of the ileal content after colectomy may contribute to the development of colonic metaplasia, leading to ileal lesions both in the pouch and in the neo-terminal ileum after IRA.

Amplification of the miR-181c/d cluster is inversely correlated with PDCD4 expression in gastric cancer

miR-181c/d is dysregulated in gastric cancer(GC).We investigated the amplification and expression of miR-181c/d and its predicted target genes in GC.Amplification of miR-181c/d was quantified by genomic real-time PCR in GC and adjacent normal tissues,as well as the levels of mature miR-181c/d was performed by real-time PCR in the same tissues.The potential target genes of miR-181c/d were predicted using bioinformatics software.Expression of one potential target gene,PDCD4,was measured by semiquantitative RT-PCR,real-time PCR,and immunohistochemistry.Next,the relationship between miR181c/d expression and PDCD4 expression was analyzed.Results indicated that the amplification and expression of miR-181c/d were significantly higher in GC than in adjacent normal tissues(primary miR-181c/d,P\0.001;miR-181c,P=0.0344;miR-181d,P=0.0153),and there was a strong correlation between mature miR-181c/d and primary miR-181c/d.Thirty-two target genes were predicted,including PDCD4 which is a known tumor suppressor gene.Expression of PDCD4 was significantly down-regulated in GC as compared to adjacent normal tissues and was inversely correlated with miR-181c/d expression in GC(miR-181c and PDCD4:R=-0.496,P=0.008;miR-181d and PDCD4:R=-0.454,P=0.003).Therefore,miR-181c/d may play a pivotal role in the pathogenesis of GC by downregulating PDCD4 expression.

Epigenetic regulation of Wnt signaling pathway gene SRY-related HMG-box 17 in papillary thyroid carcinoma

Background SRY-related HMG-box 17 （SOX17） encodes a member of the SOX （SRY-related HMG-box） family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. Recently, it was considered as a tumor suppressor gene to inhibit canonical Wnt/β-catenin signaling pathway in several malignancies. However, the function of SOX17 in thyroid cancer was unknown. Therefore, we investigated the epigenetic changes and the function of SOX17 in thyroid cancer. Methods The methylation status of the promoter region of SOX17 was detected using methylation-specific PCR in 63 papillary thyroid carcinoma （PTC） tissue, 10 normal thyroid tissue, and two thyroid cancer cell lines. Semi-quantitative RT-PCR was used to assess mRNA expression of SOX17 before and after 5-aza-2＇-deoxycytidine treatment in thyroid cancer cell lines. Expression of SOX17 and β-catenin were detected by immunohistochemistry in PTC and adjacent tissue. Luciferase reporter assay, colony formation, transfection, and Western blotting were employed to analyze the effect of SOX17 on thyroid cancer cell proliferation and the function of SOX17 in the Wnt signal pathway. Results Loss of SOX17 expression was correlated to the promoter region hypermethylation in thyroid cancer cell lines. Re-expression of SOX17 was found in TPC-1 cell line after 5-aza-2＇-deoxycytidine treatment. In primary thyroid cancer, 60.3% （38/63） were methylated and 39.7% （25/63） unmethylated. But no methylation was found in noncancerous thyroid tissues. Methylation of SOX17 was associated reversely with β-catenin expression in the cytoplasm or nucleus significantly in the PTC （P 〈0.05）. Colony formation was inhibited by re-expression of SOX17 in TPC-1 cells. SOX17 suppressed the Wnt signaling pathway and the HMG domain was essential for this effect. Conclusions SOX17 was frequently methylated in human PTC. Loss of SOX17 expression was induced by promoter region hypermethylation. SOX17 inhibited thyroid cancer proliferation. Methylation of SOX17 activated the Wnt signaling pathway in human thyroid cancer.

Current Modalities of Fibrosis Assessment in Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a burgeoning global health concern.In the subset of NAFLD patients with non-alcoholic steatohepatitis (NASH),the presence of significant fibrosis at index assessment is associated with poor prognosis and increased mortality.Hence,there is a growing need to accurately assess and stage fibrosis.Liver biopsy,the current gold standard,has limitations with sampling error and is invasive,with associated inherent risk.This has led to a host of non-invasive means of assessing fibrosis,which has garnered relevance in a disease that requires serial assessment of fibrosis longitudinally over time.This review discusses,comprehensively,the various tools available to the clinician for the assessment of fibrosis,including the various scoring systems used in liver biopsy,the non-invasive means of serum biomarkers,such as the highly-validated NAFLD fibrosis score,and the imaging-based modalities,such as transient elastography and magnetic resonance elastography.

Clinicopathological significance of altered metallothionein 2A expression in gastric cancer according to Lauren＇s classification

Background Dysregulated metallothionein 2A （MT2A） has been implicated in carcinogenesis. The purpose of this study was to investigate the expression of MT2A in gastric cancer （GC） and its correlation with prognosis. Methods Reverse transcription-polymerase chain reaction and real-time polymerase chain reaction were used to detect the mRNA expression of MT2A in 12 GC cell lines, normal gastric epithelial GES-1 cells, and 36 GC and adjacent normal tissues. MT2A protein expression was determined in 258 GC tissues and 171 adjacent normal tissues by immunohistochemistry. Results MT2A mRNA expression was lower in GC cells and primary tumors than in GES-1 cells and adjacent normal tissues, respectively, High protein expression of MT2A was present in 130 of 171 normal tissues （76.0%） and in 56 of 258 GC tissues （21,7%; P 〈0.001）. MT2A protein expression was higher in well/moderately differentiated GC （22/54; 40.7%） than in poorly differentiated GC （34/204; 16.7%; P 〈0.001）. Moreover, the protein expression of MT2A was lower in diffuse-type GC （6/82; 7.3%） than in intestinal-type GC （50/176; 28.4%; P=0.0001）. Importantly, MT2A expression was an independent prognostic factor for GC, and decreased MT2A expression was associated with poor clinical outcome （P 〈0.001）. The expression status of MT2A could predict prognosis in intestinal and diffuse-type GCs. Conclusion Expression status of MT2A might be a useful prognostic biomarker for GC, especially when used in combination with Lauren＇s classification.

Pharmacomicrobiomics： a novel route towards personalized medicine？

Inter-individual heterogeneity in drug response is a serious problem that affects the patient＇s wellbeing and poses enormous clinical and financial burdens on a societal level. Pharmacogenomics has been at the forefront of research into the impact of individual genetic background on drug response variability or drug toxicity, and recently the gut microbiome, which has also been called the second genome, has been recog- nized as an important player in this respect. Moreover, the microbiome is a very attractive target for improving drug efficacy and safety due to the opportunities to manipulate its composition. Pharmacomicrobiomics is an emerging field that investigates the interplay of microbiome variation and drugs response and disposi- tion （absorption, distribution, metabolism and excretion）. In this review, we provide a historical overview and examine current state-of-the-art knowledge on the complex interactions between gut microbiome, host and drugs. We argue that combining pharmacogenomics and pharmacomicrobiomics will provide an important foundation for making major advances in personalized medicine.

Greater Biosynthetic Liver Dysfunction in Primary Sclerosing Cholangitis Suggests Co-existent or Impending Cholangiocarcinoma

Background and Aim:Patients with primary sclerosing cholangitis (PSC) who develop cholangiocarcinoma (CCA)have a median survival of less than 6 months.In half of cases,PSC and CCA will be diagnosed either concurrently or within a year of one another.The aim of the present study is to demonstrate that the degree of biochemical liver dysfunction is associated with concomitant or impending CCA.Methods:We did a chart review of patients diagnosed with PSC and CCA up to 18 months from presentation (“CCA” group) as well as patients with PSC that underwent transplantation with no sign of CCA in their explanted liver (“nCCA” group).Along with demographic data and follow-up length,we recorded their presenting liver function tests,including alanine and aspartate aminotransferases (ALT,AST),total bilirubin (TBil),alkaline phosphatase (ALP),international normalization ratio (INR),and serum Ca 19-9 levels.Differences between mean values of the two groups were analyzed with a student's t-test.Results:Twenty-four patients were included.The “CCA”group consisted of eight patients,and the “non-CCA” group had 16 patients.There was no significant difference between the two groups in their presenting values of ALT,ALP,or serum Ca 19-9.However,the “CCA” group had significantly higher levels of AST,TBil,and INR.Conclusion:Patients with PSC and concurrent or impending CCA appear to exhibit significantly greater biochemical liver dysfunction than those who do not develop CCA.Therefore,newly-diagnosed PSC patients presenting with these findings may warrant more rigorous evaluation.