Involvement of 90-kuD ribosomal S6 kinase in collagen type I expression in rat hepatic fibrosis

AIM： To investigate the relationship between 90-kuD ribosomal $6 kinase （pg0RSK） and collagen type I expression during the development of hepatic fibrosis in vivo and in vitro.METHODS： Rat hepatic fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. The protein expression and cell location of p90RSK and their relationship with collagen type I were determined by co-immunofluoresence and confocal microscopy.Subsequently, RNAi strategy was employed to silence p90RSK mRNA expression in HSC-T6, an activated hepatic stellate cell （HSC） line. The expression of collagen type I in HSC-T6 cells was assessed by Western blotting and real-time polymerase chainreaction. Furthermore, HSCs were transfected with expression vectors or RNAi constructs of p90RSK to increase or decrease the p90RSK expression, thencollagen type I promoter activity in the transfected HSCs was examined by reporter assay. Lastly HSC-T6 cells transfected with p90RSK siRNA was treated withor without platelet-derived growth factor （PDGF）-BB at a final concentration of 20μg/L and the cell growthwas determined by MTS conversion.RESULTS： In fibrotic liver tissues, p90RSK was over-expressed in activated HSCs and had a significantpositive correlation with collagen type I levels.In HSC-T6 cells transfected with RNAi targeted top90RSK, the expression of collagen type I was down-regulated （61.8% in mRNA, P 〈 0.01, 89.1% inprotein, P 〈 0.01）. However, collagen type ] promoteractivity was not increased with over-expression of p90RSK and not decreased with low expression either,compared with controls in the same cell line （P = 0.076）.Furthermore, p90RSK siRNA exerted the inhibitionof HSC proliferation, and also abolished the effect of PDGF on the HSC proliferation.CONCLUSION： p90RSK is over-expressed in activatedHSCs and involved in regulating the abnormalexpression of collagen type I through initiating theproliferation of HSCs.     

Glycyrrhizic acid inhibits apoptosis and fibrosis in carbontetrachloride-induced rat liver injury

AIM:To investigate anti-apoptotic effects of glycyrrhizic acid(GA) against fibrosis in carbon tetrachloride(CCl4)-induced liver injury and its contributing factors.METHODS:Liver fibrosis was induced by administration of CCl4 for 8 wk.Pathological changes in the liver of rats were examined by hematoxylin-eosin staining.Collagen fibers were detected by Sirius red staining.Hepatocyte apoptosis was determined by TUNEL assay and the expression levels of cleaved caspase-3,Bax,α-SMA,connective tissue growth factor(CTGF),matrix metalloproteinase(MMP) 2 and MMP9 proteins were evaluated by western blot analysis,and α-SMA m RNA,collagen type Ⅰ and Ⅲ m RNA were estimated by real-time PCR.RESULTS:Treatment with GA significantly improved the pathological changes in the liver and markedly decreased the positive area of Sirius red compared with rats in the CCl4-treated group.TUNEL assay showed that GA significantly reduced the number of TUNEL-positive cells compared with the CCl4-treated group.The expression levels of cleaved caspase-3,Bax,α-SMA,CTGF,MMP2 and MMP9 proteins,and α-SMA m RNA,collagen type Ⅰ and Ⅲ m RNA were also significantly reduced by GA compared with the CCl4-treated group(P 0.05).CONCLUSION:GA treatment can ameliorate CCl4-induced liver fibrosis by inhibiting hepatocyte apoptosis and hepatic stellate cell activation.     

Small bowel volvulus as a complication of von Recklinghausen’s disease:A case report

We report the case of a 25-year-old male with Neurofibromatosis typeⅠ(NF-1),who presented at the time of admission with clinical findings of an acute abdomen caused by a mechanical obstruction.Computerized tomography showed a volvulus of the terminal ileum with mesenteric swirling as the cause of the patient’s symptoms.Consecutive exploratory laparotomy confirmed the diagnosis and 70 cm of the small intestine was resected due to an affection of the mesentery by multiple neurofibromas.The gastrointestinal tract is affected in approximately 10%of patients with NF-1,however the mesentery is almost always spared.Here we describe the unique case of a patient with a volvulus caused by mesenteric manifestation of von Recklinghausen’s disease,emphasizing the role of surgery in a team of multidisciplinary specialists to treat this multiorganic disease.     

Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells

AIM: To investigate the potential mechanism of Arg-Gly-Asp (RGD) peptide-labeled liposome loading oxymatrine (OM) therapy in CCl₄-induced hepatic fibrosis in rats.METHODS: We constructed a rat model of CCl₄-induced hepatic fibrosis and treated the rats with different formulations of OM. To evaluate the antifibrotic effect of OM, we detected levels of alkaline phosphatase, hepatic histopathology (hematoxylin and eosin stain and Masson staining) and fibrosis-related gene expression of matrix metallopeptidase (MMP)-2, tissue inhibitor of metalloproteinase (TIMP)-1 as well as type I procollagen via quantitative real-time polymerase chain reaction. To detect cell viability and apoptosis of hepatic stellate cells (HSCs), we performed 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay and flow cytometry. To reinforce the combination of oxymatrine with HSCs, we constructed fluorescein-isothiocyanate-conjugated Arg-Gly-Asp peptide-labeled liposomes loading OM, and its targeting of HSCs was examined by fluorescent microscopy.RESULTS: OM attenuated CCl₄-induced hepatic fibrosis, as defined by reducing serum alkaline phosphatase (344.47 ± 27.52 U/L vs 550.69 ± 43.78 U/L, P < 0.05), attenuating liver injury and improving collagen deposits (2.36% ± 0.09% vs 7.70% ± 0.60%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). OM inhibited cell viability and induced apoptosis of HSCs in vitro. RGD promoted OM targeting of HSCs and enhanced the therapeutic effect of OM in terms of serum alkaline phosphatase (272.51 ± 19.55 U/L vs 344.47 ± 27.52 U/L, P < 0.05), liver injury, collagen deposits (0.26% ± 0.09% vs 2.36% ± 0.09%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). Moreover, in vitro assay demonstrated that RGD enhanced the effect of OM on HSC viability and apoptosis.CONCLUSION: OM attenuated hepatic fibrosis by inhibiting viability and inducing apoptosis of HSCs. The RGD-labeled formulation enhanced the targeting efficiency for HSCs and the therapeutic effect.     

Risk for gastric neoplasias in patients with chronic atrophic gastritis: a critical reappraisal

Chronic atrophic gastritis (CAG) is an inflammatory condition characterized by the loss of gastric glandular structures which are replaced by connective tissue (non-metaplastic atrophy) or by glandular structures inappropriate for location (metaplastic atrophy).Epidemiological data suggest that CAG is associated with two different types of tumors:Intestinal-type gastric cancer (GC) and type Ⅰ gastric carcinoid (TⅠGC).The pathophysiological mechanisms which lead to the development of these gastric tumors are different.It is accepted that a multistep process initiating from Helicobacter pylori-related chronic inflammation of the gastric mucosa progresses to CAG,intestinal metaplasia,dysplasia and,finally,leads to the development of GC.The TⅠGC is a gastrin-dependent tumor and the chronic elevation of gastrin,which is associated with CAG,stimulates the growth of enterochromaffin-like cells with their hyperplasia leading to the development of TⅠGC.Thus,several events occur in the gastric mucosa before the development of intestinal-type GC and/or TⅠGC and these take several years.Knowledge of CAG incidence from superficial gastritis,its prevalence in different clinical settings and possible risk factors associated with the progression of this condition to gastric neoplasias are important issues.This editorial intends to provide a brief review of the main studies regarding incidence and prevalence of CAG and risk factors for the development of gastric neoplasias.     

Effects of small interfering RNA inhibit Class Ⅰ phosphoinositide 3-kinase on human gastric cancer cells

AIM:To investigate the effects of small interfering RNA(siRNA)-mediated inhibition of Class Ⅰ phosphoinositide 3-kinase(Class Ⅰ PI3K) signal transduction on the proliferation,apoptosis,and autophagy of gastric cancer SGC7901 and MGC803 cells.METHODS:We constructed the recombinant replication adenovirus PI3K(I)-RNA interference(RNAi)-green fluorescent protein(GFP) and control adenovirus NCRNAi-GFP,and infected it into human gastric cancer cells.MTT assay was used to determine the growth rate of the gastric cancer cells.Activation of autophagy was monitored with monodansylcadaverine(MDC) staining after adenovirus PI3K(I)-RNAi-GFP and control adenovirus NC-RNAi-GFP treatment.Immunofluorescence staining was used to detect the expression of microtubule-associated protein 1 light chain 3(LC3).Mitochondrial membrane potential was measured using the fluorescent probe JC-1.The expression of autophagy was monitored with MDC,LC3 staining,and transmission electron microscopy.Western blotting was used to detect p53,Beclin-1,Bcl-2,and LC3 protein expression in the culture supernatant.RESULTS:The viability of gastric cancer cells was inhibited after siRNA targeting to the Class Ⅰ PI3K blocked Class Ⅰ PI3K signal pathway.MTT assays revealed that,after SGC7901 cancer cells were treated with adenovirus PI3K(I)-RNAi-GFP,the rate of inhibition reached 27.48% ± 2.71% at 24 h,41.92% ± 2.02% at 48 h,and 50.85% ± 0.91% at 72 h.After MGC803 cancer cells were treated with adenovirus PI3K(I)-RNAiGFP,the rate of inhibition reached 24.39% ± 0.93% at 24 h,47.00% ± 0.87% at 48 h,and 70.30% ± 0.86% at 72 h(P < 0.05 compared to control group).It was determined that when 50 MOI,the transfection efficiency was 95% ± 2.4%.Adenovirus PI3K(I)RNAi-GFP(50 MOI) induced mitochondrial dysfunction and activated cell apoptosis in SGC7901 cells,and the results described here prove that RNAi of Class Ⅰ PI3K induced apoptosis in SGC7901 cells.The results showed that adenovirus PI3K(I)-RNAi-GFP transfection induced punctate distribution of     

Seroepidemiology of Helicobacter pylori infection in elderly people in the Beijing region,China

AIM:To investigate seroepidemiology of cagA+and vacA+strains of Helicobacter pylori(H.pylori)in an elderly population in Beijing and to determine risk factors for seropositivity.METHODS:A total of 2006 elderly persons(>60years)were selected using a random cluster sampling method in different parts of the Beijing area(urban,suburban and mountainous districts).Structured questionnaires were completed during home visits,including history of H.pylori infection,history of gastrointestinal diseases,diet types,hygiene habits,occupation and economic status.Blood samples(2 mL)were collected from each participant,and serum IgG antibodies to cagA,vacA and H.pylori urease antigens were measured by immunodetection.RESULTS:The prevalence of H.pylori infection in elderly subjects was 83.4%and the typeⅠH.pylori strain infection rate was 56%.The seroprevalence for typeⅠH.pylori strain infection in urban and suburbandistricts was higher than that in the mountainous areas(P<0.001).Elderly subjects who had previously performed manual labor or were in the young-old age group(age<75 years)had a higher seroprevalence of H.pylori infection than those who had previously performed mental labor or were in the oldest-old age group(age≥75 year)(P<0.05).The typeⅠH.pylori strain infection rate in the elderly with vegetarian diets was higher than in those eating high-protein foods(P<0.001).There was no significant difference in the prevalence of H.pylori strains between male and female elderly participants(P>0.05).CONCLUSION:TypeⅠH.pylori seroprevalence is higher in elderly people.The distribution of strains of H.pylori is significantly affected by age,area and dietary habits.     

Helicobacter pylori neutrophil-activating protein:From molecular pathogenesis to clinical applications

Helicobacter pylori(H.pylori)neutrophil-activating protein(HP-NAP)was originally identified as a virulence factor of H.pylori for its ability to activate neutrophils to generate respiratory burst by releasing reactive oxygen species.Later on,HP-NAP was also found to be involved in the protection of H.pylori from DNA damage,supporting the survival of H.pylori under oxidative stress.This protein is highly conserved and expressed by virtually all clinical isolates of H.pylori.The majority of patients infected with H.pylori produced antibodies specific for HP-NAP,suggesting its important role in immunity.In addition to acting as a pathogenic factor by activating the innate immunity through a wide range of human leukocytes,including neutrophils,monocytes,and mast cells,HP-NAP also mediates adaptive immunity through the induction of T helper cell typeⅠresponses.The pro-inflammatory and immunomodulatory properties of HP-NAP not only make it play an important role in disease pathogenesis but also make it a potential candidate for clinical use.Even though there is no convincing evidence to link HP-NAP to a disease outcome,recent findings supporting the pathogenic role of HP-NAP will be reviewed.In addition,the potential clinical applications of HP-NAP in vaccine development,clinical diagnosis,and drug development will be discussed.     

Preliminary study of a new pathological evolution-based clinical hepatolithiasis classification

AIM:To investigate clinical features,treatment strategies and outcomes of patients with hepatolithiasis(HL)undergoing surgical treatment,using a new clinicalclassification.METHODS:Sixty-eight HL patients were hospitalized and treated surgically from August 2011 to December2012 and they were classified into four HL types according to pathological evolution of the disease.These four HL types included typeⅠprimary type(defined as no previous biliary tract surgery),typeⅡinflammatory type(with previous biliary tract surgery and cholangitis),typeⅢmass-forming type(HL complicated by hepatic mass-forming lesion),and typeⅣterminal type(with secondary biliary cirrhosis and resultant portal hypertension).The perioperative data including general information,imaging data,postoperative complications,and immediate and final stone clearance rate were obtained and analyzed.RESULTS:In all 68 patients,the proportion of HL typeⅠ-Ⅳwas 50%(34/68),36.8%(25/68),10.3%(7/68)and 2.8%(2/68),respectively.Abdominal pain was the main clinical manifestation in typeⅠ(88.2%),fever was predominant in typeⅡ(52.0%),the malignancy rate in typeⅢwas high(71.4%),and portal hypertension and spleen enlargement were common in typeⅣ(2/2,100.0%).Liver resection rate for typesⅠ-Ⅲwas 79.4%,72.0%and 71.4%,respectively.The overall incidence of postoperative complications was23.5%(16/68).There were no perioperative deaths.The average length of hospital stay was 12.7±7.3 d.Immediate and final stone clearance rate was 73.5%(50/68)and 89.7%(61/68),respectively.Fifty-nine of68 patients(86.8%)were followed-up for1 year after surgery,and 96.6%of these patients(57/59)had a good quality of life according to a criterion recommended for postoperative evaluation of quality of life.CONCLUSION:The pathological evolution-based clinical classification of HL has a role in optimizingtreatment strategy,and patients can benefit from thisclassification when it is used properly.     

Notch3 regulates the activation of hepatic stellate cells

AIM: To investigate whether Notch signaling is involved in liver fibrosis by regulating the activation of hepatic stellate cells (HSCs).METHODS: Immunohistochemistry was used to detect the expression of Notch3 in fibrotic liver tissues of patients with chronic active hepatitis. The expression of Notch3 in HSC-T6 cells treated or not with transforming growth factor (TGF)-β1 was analyzed by immunofluorescence staining. The expression of Notch3 and myofibroblastic marker α-smooth muscle actin (α-SMA) and collagen I in HSC-T6 cells transfected with pcDNA3.1-N3ICD or control vector were detected by Western blotting and immunofluorescence staining. Moreover, effects of Notch3 knockdown in HSC-T6 by Notch3 siRNA were investigated by Western blotting and immunofluorescence staining.RESULTS: The expression of Notch3 was significantly up-regulated in fibrotic liver tissues of patients with chronic active hepatitis, but not detected in normal liver tissues. Active Notch signaling was found in HSC-T6 cells. TGF-β1 treatment led to up-regulation of Notch3 expression in HSC-T6 cells, and over-expression of Notch3 increased the expression of α-SMA and collagen I in HSC-T6 without TGF-β1 treatment. Interestingly, transient knockdown of Notch3 decreased the expression of myofibroblastic marker and antagonized TGF-β1-induced expression of α-SMA and collagen I in HSC-T6.CONCLUSION: Notch3 may regulate the activation of HSCs, and the selective interruption of Notch3 may provide an anti-fibrotic strategy in hepatic fibrosis.     

Contribution of cardiovascular magnetic resonance in the evaluation of coronary arteries

Cardiovascular magnetic resonance(CMR) allows the nonradiating assessment of coronary arteries; to achieve better image quality cardiorespiratory artefacts should be corrected. Coronary MRA(CMRA) at the mo-ment is indicated only for the detection of abnormal coronary origin, coronary artery ectasia and/or aneu-rysms(class Ⅰ indication) and coronary bypass grafts(class Ⅱ indication). CMRA utilisation for coronary ar-tery disease is not yet part of clinical routine. However, the lack of radiation is of special value for the coronary artery evaluation in children and women. CMRA can assess the proximal part of coronary arteries in almost all cases. The best results have been observed in the evaluation of the left anterior descending and the right coronary artery, while the left circumflex, which is lo-cated far away from the coil elements, is frequently im-aged with reduced quality, compared to the other two. Different studies detected an increase in wall thickness of the coronaries in patients with type Ⅰ diabetes and abnormal renal function. Additionally, the non-contrast enhanced T1-weighed images detected the presence of thrombus in acute myocardial infarction. New tech-niques using delayed gadolinium enhanced imaging promise the direct visualization of inflamed plaques in the coronary arteries. The major advantage of CMRis the potential of an integrated protocol offering as-sessment of coronary artery anatomy, cardiac function, inflammation and stress perfusion-fibrosis in the same study, providing an individualized clinical profile of pa-tients with heart disease.     

Celiac disease markers in patients with liver diseases: A single center large scale screening study

AIM:To study the coincidence of celiac disease, we tested its serological markers in patients with various liver diseases.METHODS:Large-scale screening of serum antibodies against tissue transglutaminase (tTG), and deamidated gliadin using enzyme-linked immunosorbent assay and serum antibodies against endomysium using immunohistochemistry, in patients with various liver diseases (n = 962) and patients who underwent liver transplantation (OLTx, n = 523) was performed. The expression of tTG in liver tissue samples of patients simultaneously suffering from celiac disease and from various liver diseases using immunohistochemistry was carried out. The final diagnosis of celiac disease was confirmed by histological analysis of small-intestinal biopsy. RESULTS:We found that 29 of 962 patients (3%) with liver diseases and 5 of 523 patients (0.8%) who underwent OLTx were seropositive for IgA and IgG anti-tTG antibodies. However, celiac disease was biopsy-diagnosed in 16 patients:4 with autoimmune hepatitis type Ⅰ, 3 with Wilson's disease, 3 with celiac hepatitis, 2 with primary sclerosing cholangitis, 1 with primary biliary cirrhosis, 1 with Budd-Chiari syndrome, 1 with toxic hepatitis, and 1 with non-alcoholic steatohepatitis. Unexpectedly, the highest prevalence of celiac disease was found in patients with Wilson's disease (9.7%), with which it is only rarely associated. On the other hand, no OLTx patients were diagnosed with celiac disease in our study. A pilot study of the expression of tTG in liver tissue using immunohistochemistry documented the overexpression of this molecule in endothelial cells and periportal hepatocytes of patients simultaneously suffering from celiac disease and toxic hepatitis, primary sclerosing cholangitis or autoimmune hepatitis type Ⅰ. CONCLUSION:We suggest that screening for celiac disease may be beneficial not only in patients with associated liver diseases, but also in patients with Wilson's disease.     

Antifibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline on bile duct ligation induced liver fibrosis in rats

AIM:To investigate the preventive effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) on bile duct ligation (BDL)induced liver fibrosis in rats. METHODS:Liver fibrosis in rats was induced by BDL and AcSDKP was infused subcutaneously for 2 wkvia a osmotic minipump (Alzet 2ML4) immediately after BDL operation. After scarifying, serum and liver specimens were collected. Hematoxylin and eosin staining, Sirius red staining, enzyme linked immunosorbent assay, Western blot or real-time polymerase chain reaction were used to determinate liver functions, histological alterations, collagen deposition, mRNA expression of markers for fibroblasts, transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-7 (BMP-7). RESULTS:When compared to model rats, chronic exogenous AcSDKP infusion suppressed profibrogenicTGF-β1 signaling, α-smooth muscle actin positivity (α-SMA), fibroblast specific protein-1 (FSP-1) staining and collagen gene expression. Col Ⅰ, Col Ⅲ, matrix metalloproteinase-2, tissue inhibitors of metallopro-teinase-1 and tissue inhibitors of metalloproteinase-2 mRNA expressions were all significantly downregulated by AcSDKP infusion (2.02 ± 1.10vs 14.16 ± 6.50, 2.02 ± 0.45vs 10.00 ± 3.35, 2.91 ± 0.30vs 7.83 ± 1.10, 4.64 ± 1.25 vs 18.52 ± 7.61, 0.46 ± 0.16 vs 0.34 ± 0.12, respectively, P 0.05). Chronic exogenous AcSDKP infusion attenuated BDL-induced liver injury, inflammation and fibrosis. BDL caused a remarkable increase in alanine transaminase, aspartate transaminase, total bilirubin, and prothrombin time, all of which were reduced by AcSDKP infusion. Mast cells, collagen accumulation, α-SMA, TGF-β1, FSP-1 and BMP-7 increased. The histological appearance of liver specimens was also improved. CONCLUSION:Infusion of exogenous AcSDKP attenu-ated BDL-induced fibrosis in the rat liver. Preservation of AcSDKP may be a useful therapeutic approach in the management of liver fibrosis.     

Diagnosis and management of choledochal cyst: 20 years of single center experience

We report the first case series from Africa and the Middle East on choledochal cyst,a disease which shows significant geographical distribution with high incidence in the Asian population.In this study,the epidemiological data of the patients are presented and analyzed.Attention was paid to diagnostic imaging and its accuracy in the diagnosis and classification of choledochal cyst.Most cases of choledochal cyst disease have type?ⅠandⅣ-A cysts according to the Todani classification system,which support the etiological theories of choledochal cyst,especially Babbitt’s theory of the anomalous pancreaticobiliary duct junction,which are clearly stated.The difficulties and hazards of surgical management and methods used to avoid operative complications are clarified.Early and late postoperative complications are also included.This study should be followed by multicenter studies throughout Egypt to help assess the incidence of choledochal cysts in one of the largest populations in Africa and the Middle East.     

Mechanisms underlying the impaired contractility of diabetic cardiomyopathy

Cardiac dysfunction is a well-known consequence of diabetes,with sustained hyperglycaemia leading to the development of a cardiomyopathy that is independent of cardiovascular disease or hypertension.Animal models of diabetes are commonly used to study the pathophysiology of diabetic cardiomyopathy,with the hope that increased knowledge will lead ultimately to better therapeutic strategies being developed.At physiological temperature,left ventricular trabeculae isolated from the streptozotocin rat model of type 1 diabetes showed decreased stress and prolonged relaxation,but with no evidence that decreased contractility was a result of altered myocardial Ca2+handling.Although sarcoplasmic reticulum(SR)Ca2+reuptake appeared slower in diabetic trabeculae,it was offset by an increase in actionpotential duration,thereby maintaining SR Ca2+content and favouring increased contraction force.Frequency analysis of t-tubule distribution by confocal imaging of ventricular tissue labeled with wheat germ agglutinin or ryanodine receptor antibodies showed a reduced T-power for diabetic tissue,but the differences were minor in comparison to other models of heart failure.The contractile dysfunction appeared to be the result of disrupted F-actin in conjunction with the increased typeⅠcollagen,with decreased myofilament Ca2+sensitivity contributing to the slowed relaxation.     

Diagnosis and Management of Alcoholic Liver Disease

Alcohol is a leading cause of liver disease and is associated with significant morbidity and mortality. Several factors, including the amount and duration of alcohol consumption, affect the development and progression of alcoholic liver disease (ALD). ALD represents a spectrum of liver pathology ranging from fatty change to fibrosis to cirrhosis. Early diagnosis of ALD is important to encourage alcohol abstinence, minimize the progression of liver fibrosis, and manage cirrhosis-related complications including hepatocellular carcinoma. A number of questionnaires and laboratory tests are available to screen for alcohol intake. Liver biopsy remains the gold-standard diagnostic tool for ALD, but noninvasive accurate alternatives, including a number of biochemical tests as well as liver stiffness measurement, are increasingly being utilized in the evaluation of patients with suspected ALD. The management of ALD depends largely on complete abstinence from alcohol. Supportive care should focus on treating alcohol withdrawal and providing enteral nutrition while managing the complications of liver failure. Alcoholic hepatitis (AH) is a devastating acute form of ALD that requires early recognition and specialized tertiary medical care. Assessment of AH severity using defined scoring systems is important to allocate resources and initiate appropriate therapy. Corticosteroids or pentoxifylline are commonly used in treating AH but provide a limited survival benefit. Liver transplantation represents the ultimate therapy for patients with alcoholic cirrhosis, with most transplant centers mandating a 6 month period of abstinence from alcohol before listing. Early liver transplantation is also emerging as a therapeutic measure in specifically selected patients with severe AH. A number of novel targeted therapies for ALD are currently being evaluated in clinical trials.     

Pathogenesis of alcoholic liver disease

Alcoholic liver disease (ALD) has become one of the most critical health problems in many countries, including Japan. Liver injury in ALD ranges from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular carcinoma. Many factors are thought to contribute to the development and progression of ALD, particularly insulin resistance, generation of reactive oxygen species during alcohol metabolism, adipokines from visceral adipose tissue, and endotoxin derived from the gut. Although the pathogenesis of ALD has been widely investigated, the precise mechanisms are yet to be elucidated and many questions remain. This article reviews the possible mechanisms for the development of ALD identified to date.     

Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment

Hepatocellular carcinoma(HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or Cinfection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase Ⅰ clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC.     

Collagen proportionate area correlates to hepatic venous pressure gradient in non-abstinent cirrhotic patients with alcoholic liver disease

AIM To explore the relationship between collagen proportionate area(CPA) and portal hypertension-related clinical manifestations in alcoholic liver disease(ALD).METHODS Retrospective study with chart review of patients with ALD adressed to our center between January 2012 and December 2013 for a transjugular liver biopsy(TJLB) and hepatic hemodynamic study. Patients were included if they met the following criteria:(1) Medical indication for a liver biopsy in the setting of ALD;(2) recent( 15 d) clinical, radiological, endoscopic and biological data available; and(3) estimated follow-up of at least 6 mo. Liver tissue from cirrhotic subjects obtained from transjugular liver biopsies was stained with Picro Sirius red and computer-assisted digital image analysis to determine fibrosis density using CPA was performed. RESULTS We included 61 patients with alcoholic ALD, subdivided in 41 active alcohol drinkers and 20 durably abstinent patients. Nine healthy liver donors served as controls. Mean CPA in patients with ALD was 7.1%, with no difference between active drinkers and abstinent patients(P = 0.17). Using a fibrosis density cutoff of 5%, we observed a positive correlation between high fibrosis density and the hepatic venous pressure gradient(HVPG) only in active drinkers(P = 0.02). At 12-mo of follow-up, in the group of active alcohol drinkers, patients reaching a composite outcome showed a higher HVPG value as compared to those who did not(18.5 mm Hg vs 14.5 mm Hg P 0.04) whereas CPA values were similar(6.9% vs 11%, P = 0.23).CONCLUSION In active alcoholic ALD, CPA correlates to portal pressure but only HVPG predicts clinical events, pointing to the role of alcohol as a modulator of portal hypertension.