Impact of Helicobacter pylori Infection on the Pathogenesis and Management of Nonalcoholic Fatty Liver Disease

Helicobacter pylori(H.pylori)infection is widely prevalent worldwide.H.pylori infection has been reported to be a risk factor for the development of insulin resistance,nonalco-holic fatty liver disease(NAFLD),nonalcoholic steatohepatitis(NASH),liver fibrosis,and cirrhosis.Because treatment for NAFLD,other than weight loss is limited,the treatment for H.pylori infection is well established.It is important to determine whether screening and treatment for H.pylori infection should be considered in patients with no gastrointestinal symptoms.The aim of this mini-review is to evaluate the association be-tween H.pylori infection and NAFLD including epidemiology,pathogenesis,and the evidence for H.pylori infection as a modifiable risk factor for preventing or treating NAFLD.

Primary Non-HFE Hemochromatosis:A Review

Iron homeostasis is a complex process in which iron uptake and use are tightly balanced.Primary Type 1 or HFE hemochromatosis results from homozygous mutations in the gene that encodes human homeostatic iron regulator(known as human factors engineering,HFE)protein,a regulator of hepcidin,and makes up approximately 90%of all hemochromatosis cases.However,four types of hemochromatosis do not involve the HFE gene.They are non-HFE hemochromatosis type 2A(HFE2,encoding HJV),type 2B(HAMP,encoding hepcidin),type 3(TFR2,encoding transferring receptor-2),and types 4A and B(SLC40A1,encoding ferroportin.NonHFE hemochromatosis is extremely rare.Pathogenic allele frequencies have been estimated to be 74/100,000 for type 2A,20/100,000 for type 2B,30/100,000 for type 3,and 90/100,000 for type 4 hemochromatosis.Current guidelines recommend that the diagnosis be made by ruling out HFE mutations,history,physical examination,laboratory values(ferritin and transferrin saturation),magnetic resonance or other imaging,and liver biopsy if needed.While less common,non-HFE hemochromatosis can cause iron overload as severe as the HFE type.In most cases,treatment involves phlebotomy and is successful if started before irreversible damage occurs.Early diagnosis and treatment are important because it prevents chronic liver disease.This review updates the mutations and their pathogenetic consequences,the clinical picture,diagnostic guidelines,and treatment of hemochromatosis.

Primary Hepatic Extra-gastrointestinal Stromal Tumors:Molecular Pathogenesis,Immunohistopathology,and Treatment

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract.They originate from the interstitial cells of Cajal and are usually found in extrahepatic gastrointestinal sites.However,a small subset are derived from the liver and are known as primary hepatic gastrointestinal stromal tumors(PHGIST).They have a poor prognosis and are historically difficult to diagnose.Our objective was to review and update the latest evidence-based knowledge concerning PHGIST,with a focus on epidemiology,etiology,pathophysiology,clinical presentation,histopathology,and treatment.These tumors are usually found incidentally,occur sporadically,and are associated with mutations of KIT and PDGFRA genes.PHGIST is a diagnosis of exclusion,as it has the same molecular,immunochemistry and histological appearance as gastrointestinal stromal tumors(GIST).Thus,imaging,such as positron emission tomography-computed tomography(PET-CT)must be used to rule out metastatic GIST before a diagnosis can be made.However,with mutation analysis and pharmacological advances,tyrosine kinase inhibitors are typically pursued with or without surgical intervention.Other potential treatments include transcatheter arterial chemoembolization and tumor ablation.However,these are typically considered palliative options.As there are only a limited number of publications regarding PHGIST,data concerning morbidity and mortality are not yet available.Immunohistopathology can help develop screening guidelines and evaluating resistance to treatment.

Seronegative Autoimmune Hepatitis

Autoimmune hepatitis(AIH)is a relatively rare liver disease with varying worldwide incidence of from 0.7 to 2 per 100,000 people.It is characterized by the presence of auto-antibodies.However,an average of 10% of AIH cases have AIH symptoms and pathology but lack autoimmune serology.For such seronegative AIH(snAIH)cases,there is currently no established diagnostic algorithm for diagnosis.and improper or delayed diagnosis of snAIH can lead to no or inappropriate treatment that results in progression to fulminant hepatitis or cirrhosis.This review aims to review the current literature and to present an update of seronegative autoimmune hepatitis,including its pathophysiology,clinical presentation,methods of diagnosis,and treatment in order to increase awareness and emphasize the necessity for timely management.

丙型肝炎病毒NS_5B在Hub-7细胞中的转染与表达

目的建立丙型肝炎病毒（ＨＣＶ）ＮＳ５Ｂ表达的人肝细胞系。方法以脂质体共转染ＮＳ５ＳＢ基因人Ｈｕｂ－７细胞，以ＰＣＲ和Ｓｏｕｔｈｅｒｎ ｂｌｏｔ在ＤＮＡ水平检测转染的结果，以ｗｅｓｔｅｒｎ ｂｌｏｔ证实了Ｈｕｂ－７细胞中有ＮＳｕＢ的蛋白表达。结累在转染过ＮＳＳＢ质粒的细胞系中有ＮＳＳＢ基因的存在和ＨＣＶ－ＲＮＡ多聚酶的表达。结论我们在Ｈｕｂ－７细胞中建立了ＨＣＶ－ＲＮＡ多聚酶表达系统，它有助于研究ＨＣＶ复制机制和为基因治疗丙型肝炎打下基础。

The Evolving Nature of Hepatic Abscess:A Review

Hepatic abscess (HA) remains a serious and often difficult to diagnose problem.HAs can be divided into three main categories based on the underlying conditions:infectious,malignant,and iatrogenic.Infectious abscesses include those secondary to direct extension from local infection,systemic bacteremia,and intra-abdominal infections that seed the portal system.However,over the years,the etiologies and risks factors for HA have continued to evolve.Prompt recognition is important for instituting effective management and obtaining good outcomes.

Hepatic Echinococcal Cysts: A Review

Cystic echinococcosis (CE) is a widely endemic helminthic disease caused by infection with metacestodes (larval stage)of the Echinococcus granulosus tapeworm.E.granulosus are common parasites in certain parts of the world,and are present on every continent with the exception of Antarctica.As a result,a large number of people are affected by CE.The increased emigration of populations from endemic areas where prevalence rates are as high as 5-10% and the relatively quiescent clinical course of CE pose challenges for accurate and timely diagnoses.Upon infection with CE,cyst formation mainly occurs in the liver (70%).Diagnosis involves serum serologic testing for antibodies against hydatid antigens,but preferably with imaging by ultrasound or CT/MRI.Treatment methods include chemotherapy with benzimidazole carbamates and/or surgical approaches,including percutaneous aspiration injection and reaspiration.The success of these methods is influenced by the stage and location of hepatic cysts.However,CE can be clinically silent,and has a high risk for recurrence.It is important to consider the echinococcal parasite in the differential diagnosis of liver cystic lesions,especially in patients of foreign origin,and to perform appropriate long-term follow-ups.The aim of this review is to highlight the epidemiology,natural history,diagnostic methods,and treatment of liver disease caused by E.granulosus.

Mechanisms and Prevention of Vertical Transmission in Chronic Viral Hepatitis

Vertical transmission (VT) is the primary route of transmission of viral hepatitis in children.The rate of VT ranges from 1-28% with hepatitis B virus (HBV) and 3-15% with hepatitis C virus (HCV).VT for both viruses can occur during the intrauterine or peripartum period.VT of HBV primarily occurs by intrauterine transmission (IUT).Hepatitis B surface antigen is unable to cross the placenta and,therefore,relies on processes like transplacental leakage,placental infection,cellular transmission by peripheral blood mononuclear cells,and germline transmission.HCV can also infect the fetus by IUT.Both viruses also have the potential for transmission during delivery,when there is increase chance of maternal-fetal blood exposure.HBV and HCV share some common risk factors for VT,including maternal viral load,human immunodeficiency virus co-infection and neonatal sex.Prevention of VT differs greatly between HBV and HCV.There are several alternatives for prevention of HBV VT,including antiviral medications during the third trimester of pregnancy and HBV vaccine,as well as hepatitis B immunoglobulin administration to infants post-partum.In contrast,there are no preventative interventions available for HCV.Despite these differences,the key to prevention with both viruses is screening women prior to and during pregnancy.

Differentiating Cystic Liver Lesions:A Review of Imaging Modalities, Diagnosis and Management

Hepatic cysts(HCs)are frequently discovered incidentally on abdominal imaging.The prevalence of HCs has been reported as high as 15–18%in the United States.Although most cysts are benign,some are malignant or premalignant.It is impor-tant to diagnose cystic lesions in order to properly manage them.Imaging with conventional ultrasound,computed to-mography,magnetic resonance imaging,or contrast-enhanced ultrasound can be used to further characterize and diagnose HCs.Ultrasound is typically the first-line imaging modality,whereas more advanced imaging can help narrow down the specific lesion.Contrast-enhanced ultrasound is a newer mo-dality,recently approved in the United States,which offers non-invasive evaluation in real-time.The first step in diagnosis is stratifying risk by differentiating simple and complex cysts.There are several features that can help identify HCs,including septae,mural consistency,calcifications,and quality of cystic fluid.Simple cysts are mainly congenital cysts,but also occur in polycystic liver disease.Complex cysts include mucinous neoplasms,echinococcal cysts,hemorrhagic cysts,cystic hep-atocellular carcinoma and other rare lesions.Treatment is indicated in symptomatic cysts or those suspicious for malig-nant or premalignant features.Treatment modalities include fenestration,aspiration sclerotherapy,or surgical resection.

HBV-HCV Coinfection: Viral Interactions, Management, and Viral Reactivation

Hepatitis B virus(HBV)and hepatitis C virus(HCV)coinfec-tion is a complex clinical entity that has an estimated world-wide prevalence of 1–15%.Most clinical studies have shown that progression of disease is faster in HBV-HCV coinfected patients compared to those with monoinfection.Hepatocel-lular carcinoma development appears to have higher rate in coinfections.Viral replication in coinfected cells is character-ized by a dominance of HCV over HBV replication.There are no established guidelines for treatment of HBV-HCV coinfec-tion.Studies on interferon-based therapies and direct-acting antivirals have shown varying levels of efficacy.Clinical reports have indicated that treatment of HCV without sup-pression of HBV increases the risk for HBV reactivation.In this review,we appraise studies on both direct-acting antivirals and interferon-based therapies to evaluate the efficacy and rates of reactivation with each regimen.Screening for and prevention of coinfection are important to prevent serious HBV reactivations.

Cytomegalovirus Hepatitis in Immunocompetent and Immunocompromised Hosts

Human cytomegalovirus (HCMV) infection is common and affects between 40–100% of the worldwide population. However, the majority of cases are asymptomatic and when severe disease occurs, it is usually restricted to immunocompromised patients. Liver involvement by HCMV differs significantly, accordingly to the immune status of the host. In immunocompromised patients, particularly liver transplant patients, it often causes clinically significant hepatitis. On the other hand, in immunocompetent patients, HCMV hepatitis requiring hospitalization is extremely rare. This review aims to appraise studies regarding the pathophysiology of HCMV hepatitis, including mechanisms of latency and reactivation and its contribution to disease development, clinical presentation, diagnostic modalities and treatment, with a focus on comparing different aspects between immunocompromised and immunocompetent hosts.

Update on Sphincter of Oddi Dysfunction: A Review

Sphincter of Oddi dysfunction(SOD)encompasses a spectrum of clinical syndromes that are not fully understood,and various diagnostic and therapeutic methods have had varying results depending on the type of dysfunction.This review explored various mechanisms that might play a role in SOD and methods of diagnosis and management.It is important to rule out other causes of abdominal pain with laboratory testing,imaging studies,and endoscopic procedures.Medications that affect sphincter motility should be identified as well.Manometry is the gold standard for diagnosis but it is not always required.For example,patients with type I SOD may have symptomatic improvement with sphincterotomy without need for a diagnostic manometry.Hepatobiliary scintigraphy and fatty meal sonography may also have diagnostic utility.Sphincterotomy is not always effective for symptomatic improvement in type II and III SOD.Alternate therapies with calcium channel blockers and botulinum toxin have been studied and might be considered as options after discussing the risks and benefits with the patients.

HEV and HBV Dual Infection:A Review

Hepatitis E virus(HEV)is a global health problem,affecting about 20 million people worldwide.There is significant overlap of hepatitis B virus(HBV)and HEV endemicity in many Asian countries where dual infections with HEV and HBV can occur.Though the clinical course of HEV is largely self-limited,HEV superinfection in patients with chronic hepatitis B(CHB)can result in acute exacerbation of underlying CHB.HEV superinfection in patients with CHB-related cirrhosis has been identified as a risk factor for decompensated cirrhosis and an independent predictor of mortality.Whereas acute HEV infection in pregnancy can cause fulminant liver failure,the few studies on pregnant patients with dual HBV and HEV infection have shown a subclinical course.Immunosuppression is a risk factor for the development of chronic HEV infection,which can be managed by decreasing the dose of immune-suppressants and administering ribavirin.Vaccination for HEV has been developed and is in use in China but its efficacy in patients with CHB has yet to be established in the USA.In this review,we appraise studies on dual infection with HEV and HBV,including the effect of HEV superinfection and coinfection in CHB,management strategies used and the role of active vaccination in the prevention of HEV.

Evidence for Viral Induction of Biliary Atresia: A Review

Biliary atresia(BA)is a childhood disease which manifests with abnormal narrowing,blockage or complete absence of bile ducts within the liver.Many possible etiologies have been reported for the development of BA,including congenital,perinatal and acquired conditions.Since the 1970's,there has been increasing evidence linking BA development to viral perinatal infections.The viral vectors most commonly implicated include members of the herpesviridae family(cytomegalovirus and Epstein-Barr virus)as well as those of the reoviridae family(reovirus and rotavirus).While extensive work has been done on a murine model of disease,the current review focuses primarily on evidence from human studies of viral vectors in children afflicted with BA.

Role of Biologics in the Development of Autoimmune Hepatitis: A Review

Autoimmune hepatitis(AIH)is a cause of chronic,immunemediated liver injury which without treatment may progress to end-stage liver disease.The disease state,characterized by elevations in liver enzymes,autoantibodies,and interface hepatitis on histology,has been noted to be induced by a wide range of insults.Medications,most commonly minocycline and nitrofurantoin,have long been established as potential inducers of AIH.Recently,biologics,powerful immune-modulators,have also been reported to induce AIH.We conclude that there is an association between administration of biologics in the development of AIH,and whether the relationship is causal will require appropriate studies in the future.

The Molecular and Structural Basis of HBV-resistance to Nucleos(t)ide Analogs

Infection with hepatitis B virus(HBV)is a worldwide health problem.Chronic hepatitis B can lead to fibrosis,liver cirrhosis,and hepatocellular carcinoma(HCC).Management of the latter two conditions often requires liver transplantation.Treatment with conventional interferon or pegylated interferon alpha can clear the virus,but the rates are very low.The likelihood,however,of viral resistance to interferon is minimal.The main problems with this therapy are the frequency and severity of side effects.In contrast,nucleos(t)ide analogs(NAs)have significantly lower side effects,but require long term treatment as sustained virological response rates are extremely low.However,long term treatment with NAs increases the risk for the development of anti-viral drug resistance.Only by understanding the molecular basis of resistance and using agents with multiple sites of action can drugs be designed to optimally prevent the occurrence of HBV antiviral resistance.

Dermatologic Extrahepatic Manifestations of Hepatitis C

Hepatitis C virus (HCV) affects millions of people worldwide,and an estimated 3.2 million people in the United States.HCV is a hepatotropic and lymphotropic virus that causes not only liver disease,but also a significant number of extrahepatic manifestations (EHMs).Up to 74% of patients affected by HCV will have HCV-related EHMs of some severity in their lifetime.The EHMs vary from simple cutaneous palpable purpura to complex lymphoproliferative disorders,including lymphomas and immune-complex deposit diseases causing local and/or systemic complications.Mixed cryoglobulinemia (MC) is manifested by multiple systemic organ involvement,mainly skin,kidney,peripheral nerves,and salivary glands,and less frequently causes widespread vasculitis and malignant lymphoma.MC affects up to 3% of HCV-infected patients with cryoglobulinemia of clinical significance,i.e.>6%.Severe disease requires immunosuppressive or plasma exchange therapy.HCV prevalence in the United States in patients with porphyria cutanea tarda (PCT) was reported to be 66%,much higher than that in general population.Therefore,all patients with PCT should be screened for HCV.The skin rash of PCT varies from large blisters to small vesicles and/or milia on the hands.Skin manifestations due to PCT usually respond to anti-HCV treatment together with reducing skin sun exposure,avoiding triggers,having routine phlebotomy (especially for people with chronic iron overload states),and using chloroquine.Lichen planus (LP),which typically affects both the skin and oral mucosa is a chronic inflammatory disease of squamous cell origin affecting about 1% of the worldwide population.The prevalence of HCV in patients with LP varies based on geographic location.We review here the basic pathophysiology,clinical features,and management of dermatologic manifestations of HCV.

Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis Overlap Syndrome:A Review

Primary sclerosing cholangitis(PSC)and primary biliary cirrhosis(PBC)are slow progressive diseases which have been increasing in prevalence.The pathogeneses of PBC and PSC are incompletely understood but the underlying mechanisms appear to be fundamentally autoimmune in origin.Although PBC and PSC appear to be separate entities,overlap has been described.Diagnosis depends on a combination of serological markers,imaging,and pathological criteria.The mainstay of treatment has been ursodeoxycholic acid and in some cases of extrahepatic biliary obstruction and overlap disorder,endoscopic retrograde cholangiopancreatography has been useful.

Hepatitis C Virus: A Review of Treatment Guidelines,Cost-effectiveness, and Access to Therapy

Hepatitis C virus (HCV) infection remains a significant medical concern in the United States and around the world.It is still one of the leading causes of chronic liver disease,and,for more than 20 years,there has been little progress in the treatment of HCV infection.The advent of direct-acting antivirals (DAAs) initiated the era of high efficacy and well-tolerated medications with high cure rates.The efficacy of these medications has prompted many professional societies around the world to update their treatment guidelines to include DAAs as first-line treatment.Guidelines by the American Association for the Study of Liver Disease/Infectious Disease Society of America,World Health Organization,Asian-Pacific Association for the Study of Liver and the European Association for the Study of Liver have all incorporated DAAs into their treatment guidelines.Despite the promising data supporting these medications,however,their cost represents a limiting factor to their use,even though studies have shown DAAs to be cost-effective.In addition to the expense of these medications and limited resources,there are many barriers preventing patients from receiving this potentially life-saving treatment.In order to overcome these barriers,these issues need to be recognized and addressed.

Persistently Rising Alpha-fetoprotein in the Diagnosis of Hepatocellular Carcinoma:A Review

Hepatocellular carcinoma(HCC),one of the most common malignant tumors worldwide,is known for its grim prognosis,with untreated life expectancy being only a matter of months after the diagnosis.The difficulty in making a diagnosis early is one of the main contributing factors to the poor prognosis.Alpha-fetoprotein(AFP)had long been used as a surveillance tool,but suboptimal specificity and sensitivity has prompted liver societies to abandon the recommendation for its universal use,even in combination with ultrasonography.Most studies have shown no obvious correlation between serum AFP level and HCC tumor size,stage,or survival post-diagnosis.However,some studies concluded that a gradual rise or persistent elevation in AFP were positive predictors for tumor development.Other studies reported a fall in AFP followed by a rise in patients with HCC as well as persistently rising AFP levels without development of HCC on follow up.Our calculation of the sensitivity and specificity of persistently rising AFP for HCC were both low,at 60%and 35.8%,respectively,indicating that the presence of persistently rising AFP per se did not offer diagnostic benefit.In addition,our calculated mean slopes of persistently rising AFP levels in HCC and non-HCC patients were numerically very different,but the difference was not statistically significant.We conclude that the published data do not support a role for rising AFP levels per se in the diagnosis of HCC.