Animal models for the study of hepatitis C virus infection and replication

Hepatitis C virus (HCV) hepatitis, initially termed non-A, non-B hepatitis, has become one of the leading causes of cirrhosis and hepatocellular carcinoma worldwide. With the help of animal models, our understanding of the virus has grown substantially from the time of initial discovery. There is a paucity of available animal models for the study of HCV, mainly because of the selective susceptibility limited to humans and primates. Recent work has focused modification of animals to permit HCV entry, replication and transmission. In this review, we highlight the currently available models for the study of HCV including chimpanzees, tupaia, mouse and rat models. Discussion will include methods of model design as well as the advantages and disadvantages of each model. Particular focus is dedicated to knowledge of pathophysiologic mechanisms of HCV infection that have been elucidated through animal studies. Research within animal models is critically important to establish a complete understanding of HCV infection, which will ultimately form the basis for future treatments and prevention of disease.

Non-alcoholic fatty liver disease and the metabolic syndrome:Effects of weight loss and a review of popular diets,Are low carbohydrate diets the answer?

Non-alcoholic fatty liver disease （NAFLD） encompasses a wide spectrum of fat-induced liver injury, ranging from relatively benign steatosis to cirrhosis and liver failure. The presence of obesity and insulin resistance is strongly associated with non-alcoholic fatty liver and confers on it a greater risk of histologically advanced disease. There is a growing concern in the medical profession as the prevalence of this disease continues to rise in parallel with the rise in obesity and the metabolic syndrome. Treatment options are limited and dietary weight loss is often advised. Low fat diets are difficult to adhere to and recent studies have shown the potential of low carbohydrate diets for weight loss and improving insulin resistance. Thus far, no study has evaluated the effect of low carbohydrate diets on NAFLD. Future studies will be required to address this question and others with regards to the nutritional adequacy and long-term side effects of these diets.

Inhibition of hepatitis C virus replication by single-stranded RNA structural mimics

AIM: To examine the effect of hepatitis C virus (HCV) structural mimics of regulatory regions of the genome on HCV replication.METHODS: HCV RNA structural mimics were constructed and tested in a HCV genotype 1b aBB7 replicon,and a Japanese fulminant hepatitis-1 (JFH-1) HCV genotype 2a infection model.All sequences were computer-predicted to adopt stem-loop structures identical to the corresponding elements in full-length viral RNA.Huh7.5 cells bearing the BB7 replicon or infected with JFH-1 virus were transfected with expression vectors generating HCV mimics and controls.Cellular HCV RNA and protein levels were quantified by real-time polymerase chain reaction and Western blotting,respectively.To evaluate possible antisense effects,complementary RNAs spanning a mimic were prepared.RESULTS: In the BB7 genotype 1b replicon system,mimics of the polymerase (NS-5B),X and BA regions inhibited replication by more than 90%,50%,and 60%,respectively.In the JFH-1 genotype 2 infection system,mimics that were only 74% and 46% identical in sequence relative to the corresponding region in JFH-1 inhibited HCV replication by 91.5% and 91.2%,respectively,as effectively as a mimic with complete identity to HCV genotype 2a.The inhibitory effects were confirmed by NS3 protein levels.Antisense RNA molecules spanning the 74% identical mimic had no significant effects.CONCLUSION: HCV RNA structural mimics can inhibit HCV RNA replication in replicon and infectious HCV systems and do so independent of close sequence identity with the target.

Sessile serrated adenomas in the proximal colon are likely to be flat,large and occur in smokers

AIM:To examine the epidemiology and the morphology of the proximal sessile serrated adenomas(SSAs).METHODS:We conducted a retrospective study to identify patients with SSAs using a university-based hospital pathology database query from January 2007to April 2011.Data collected included:age,gender,ethnicity,body mass index,diabetes,smoking,family history of colorectal cancer,aspirin,and statin use.We collected data on morphology of SSAs including site(proximal or distal),size,and endoscopic appearance(flat or protuberant).We also compared proximal SSAs to proximal tubular adenomas detected during same time period.RESULTS:One hundred and twenty patients with SSAs were identified:61%were distal and 39%were proximal SSAs.Proximal SSAs were more likely to be flat than distal(100%vs 78%respectively;P=0.0001).Proximal SSAs were more likely to occur in smokers(OR=2.63;95%CI:1.17-5.90;P=0.02)and in patients with family history of colorectal cancer(OR=4.72;95%CI:1.43-15.55;P=0.01)compared to distal.Proximal SSAs were statistically more likely to be≥6 mm in size(OR=2.94;P=0.008),and also more likely to be large(≥1 cm)(OR=4.55;P=0.0005)compared to the distal lesions.Smokers were more likely to have proximal(P=0.02),flat(P=0.01)and large(P=0.007)SSAs compared to non-smokers.Compared to proximal tubular adenomas,proximal SSAs were more likely to be large and occur in smokers.CONCLUSION:Proximal SSAs which accounted for two-fifths of all SSAs were more likely to present as flat lesions,larger SSAs,and were more likely to occur in smokers and in patients with family history of colorectal cancer.Our data has implications for colorectal cancer screening.

An ironic case of liver infections:Yersinia enterocolitis in the setting of thalassemia

A 49 years old Vietnamese male with a history of thalassemia,presented with gastrointestinal symptoms and signs of hemolysis.He was diagnosed with yersinia enterocolitis.Yersinia is a gram-negative rod that most frequently occurs in children especially during the winter months.In the current case,the bone marrow biopsy showed hemophagocytosis along with positive cultures for Yersinia.The microorganism likely triggered hemophagocytosis.This syndrome,also known as,hemophagocytic lymphohistiocytosis,is defined by fever for more than 7 d,cytopenia of two or more cell lines,hemophagocytosis,hepatitis,serum ferritin greater than500,jaundice,lymphadenopathy,and hepatosplenomegaly.This disorder can be either familial or secondary to a strong immunologic activation.Both have an overwhelming activation of T-cells and macrophages.

Anabolic androgenic steroid-induced liver injury:An update

Anabolic androgenic steroids(AASs)are a group of molecules including endogenous testosterone and synthetic derivatives that have both androgenic and anabolic effects.These properties make them therapeutically beneficial in medical conditions such as hypogonadism.However,they are commonly bought illegally and misused for their anabolic,skeletal muscle building,and performanceenhancing effects.Supraphysiologic and long-term use of AASs affects all organs,leading to cardiovascular,neurological,endocrine,gastrointestinal,renal,and hematologic disorders.Hepatotoxicity is one of the major concerns regarding AASs treatment and abuse.Testosterone and its derivatives have been most often shown to induce a specific form of cholestasis,peliosis hepatis,and hepatic benign and malignant tumors.It is currently believed that mechanisms of pathogenesis of these disorders include disturbance of antioxidative factors,upregulation of bile acid synthesis,and induction of hepatocyte hyperplasia.Most toxicity cases are treated with supportive measures and liver function normalizes with discontinuation of AAS.However,some long-term consequences are irreversible.AAS-induced liver injury should be taken in consideration in patients with liver disorders,especially with the increasing unintentional ingestion of supplements containing AAS.In this paper,we review the most current knowledge about AAS-associated adverse effects on the liver,and their clinical presentations,prevalence,and pathophysiological mechanisms.

Pathogenesis of Thrombocytopenia in Chronic HCV Infection:A Review

A large proportion of patients with chronic hepatitis C have associated thrombocytopenia (TCP). Due to bleeding risks, TCP, when severe, can limit diagnostic and therapeutic procedures, treatments, and increases risk of complications, especially excessive bleeding. It is important to understand the mechanisms that cause TCP in order to manage it. In general, TCP can be due to increased destruction or decreased production. Proposed mechanisms of increased destruction include autoantibodies to platelets and hyper-splenism with sequestration. Proposed mechanisms of de-creased production include virus-induced bone marrow suppression and decreased TPO production. Autoantibodies directed against platelet surface antigens have demonstrated an inverse correlation with platelet counts. Hypersplenism with sequestration involves the interaction of portal hyper-tension, splenomegaly, and platelet destruction. Decreased production mechanisms involve appropriate and inappropri-ate levels of TPO secretion. There is limited evidence to support viral-induced bone marrow suppression. In contrast, there is strong evidence to support low levels of TPO in liver failure as a major cause of TCP. TPO-agonists, specifically eltrombopag, have been shown in hepatitis C patients to increase platelet counts without reducing portal hypertension or splenomegaly. We conclude that TCP in hepatitis C virus-induced liver disease is often multifactorial, but an under-standing of the mechanisms can lead to judicious use of new drugs for treatment.

Mechanisms of Hepatic Cholestatic Drug Injury

Drug-induced cholestasis represents a form of drug-induced liver disease that can lead to severe impairment of liver function.Numerous drugs have been shown to cause cholestasis and consequently bile duct toxicity.However,there is still lack of therapeutic tools that can prevent progression to advanced stages of liver injury.This review focuses on the various pathological mechanisms by which drugs expresstheir hepatotoxic effects,as well as consequences of increased bile acid and toxin accumulation in the hepatocytes.

Drug-induced Fatty Liver Disease:Pathogenesis and Treatment

Metabolic dysfunction-associated fatty liver disease(commonly known as MAFLD)impacts global health in epidemic proportions,and the resulting morbidity,mortality and economic burden is enormous.While much attention has been given to metabolic syndrome and obesity as offending factors,a growing incidence of polypharmacy,especially in the elderly,has greatly increased the risk of drug-induced liver injury(DILI)in general,and drug-induced fatty liver disease(DIFLD)in particular.This review focuses on the contribution of DIFLD to DILI in terms of epidemiology,pathophysiology,the most common drugs associated with DIFLD,and treatment strategies.

HCV Extrahepatic Manifestations

Hepatitis C virus(HCV)has been shown to affect many tissues other than liver.However,of the many extrahepatic manifestations(EMs)that have been associated with HCV,including cryoglobulinemia,lymphoma,insulin resistance,type 2 diabetes and neurological disorders,only a few have been shown to be directly related to HCV infection of extrahepatic tissues.HCV-triggered immune-mediated mechanisms account for most of the EMs.It is estimated that up to 74%of patients with chronic hepatitis C can develop at least one EM.All HCV patients with EMs should be considered for antiviral therapy,although not all will resolve with sustained virological response.