Subnormal Serum Liver Enzyme Levels:A Review of Pathophysiology and Clinical Significance

Subnormal levels of liver enzymes,below the lower limit of normal on local laboratory reports,can be useful diagnostically.For instance,subnormal levels of aminotransferases can be observed in vitamin B6 deficiency and chronic kidney disease.Subnormal alkaline phosphatase levels may indicate the presence of hypophosphatasia,Wilson's disease,deficiencies of divalent ions,or malnutrition.Subnormal levels of gamma glutamyl transferase may be seen in cases of acute intrahepatic cholestasis,the use of certain medications,and in bone disease.Finally,subnormal levels of 5'-nucleotidase have been reported in lead poisoning and nonspherocytic hemolytic anemia.The aim of this review is to bring attention to the fact that subnormal levels of these enzymes should not be ignored as they may indicate pathological conditions and provide a means of early diagnosis.

Heritable Chronic Cholestatic Liver Diseases:A Review

Chronic cholestasis due to heritable causes is usually diagnosedin childhood.However,many cases can present andsurvive into adulthood.The time course varies considerablydepending on the underlying etiology.Laboratory data usuallyreveal elevated conjugated hyperbilirubinemia,alkalinephosphatase,and gamma-glutamyl transpeptidase.Patientsmay be asymptomatic;however,when present,the typicalsymptoms are pruritus,jaundice,fatigue,and alcoholicstools.The diagnostic methods and management requireddepend on the underlying etiology.The development of genome-wide associated studies has allowed the identificationof specific genetic mutations related to the pathophysiologyof cholestatic liver diseases.The aim of this review was tohighlight the genetics,clinical pathophysiology,presentation,diagnosis,and treatment of heritable etiologies of chroniccholestatic liver disease.

Etiologies of Splenic Venous Hypertension:A Review

Splenic venous hypertension or left-sided portal hypertension is a rare condition caused by an obstruction of the splenic vein.Usually,it presents with upper gastrointestinal bleeding in the absence of liver disease.Etiologies can be classified based on the mechanism of development of splenic vein hypertension:compression,stenosis,inflammation,thrombosis,and surgically decreased splenic venous flow.Diagnosis is established by various imaging modalities and should be suspected in patients with gastric varices in the absence of esophageal varices,splenomegaly,or cirrhosis.The management and prognosis vary depending on the underlying etiology but generally involve reducing splenic venous pressure.The aim of this review was to summarize the etiologies of splenic venous hypertension according to the mechanism of development.

Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review

Gallstone(GS)disease is common and arises from a combination of genetic and environmental factors.Although genetic abnormalities specifically leading to cholesterol GSs are rare,there are clinically significant gene variants associated with cholesterol GSs.In contrast,most bilirubin GSs can be attributed to genetic defects.The pathogenesis of cholesterol and bilirubin GSs differs greatly.Cholesterol GSs are notably influenced by genetic variants within the ABC protein superfamily,including ABCG8,ABCG5,ABCB4,and ABCB11,as well as genes from the apolipoprotein family such as ApoB100 and ApoE(especially the E3/E3 and E3/E4 variants),and members of the MUC family.Conversely,bilirubin GSs are associated with genetic variants in highly expressed hepatic genes,notably UGT1A1,ABCC2(MRP2),ABCC3(MRP3),CFTR,and MUC,alongside genetic defects linked to hemolytic anemias and conditions impacting erythropoiesis.While genetic cases constitute a small portion of GS disease,recognizing genetic predisposition is essential for proper diagnosis,treatment,and genetic counseling.

Unique Genetic Features of Lean NAFLD: A Review of Mechanisms and Clinical Implications

Non-alcoholic fatty liver disease(NAFLD)affects 25%of the global population.About 20%have a normal body mass index(BMI)and a variant known as lean NAFLD.Unlike typical NAFLD cases associated with obesity and diabetes,lean NAFLD causes liver disease by mechanisms not related to excess weight or insulin resistance.Genetic disorders are among the major factors in developing lean NAFLD,and genome-wide association studies have identified several genes associated with the condition.This review aims to increase awareness by describing the genetic markers linked to NAFLD and the defects involved in developing lean NAFLD.

Effects of Transjugular Intrahepatic Portosystemic Shunt on Renal and Pulmonary Function in Hepatic Decompensation with and without Hepatorenal and Hepatopulmonary Syndromes:A Review

Cirrhosis is often characterized by decreased liver function,ranging from a compensated,typically asymptomatic phase to a decompensated phase characterized by the appearance of ascites or variceal bleeding,and ultimately hepatorenal syndrome(HRS)or hepatopulmonary syndrome(HPS).The latter two complications are associated with a poor prognosis and limited treatment efficacy.In cases of ascites or variceal bleeding resistant to medical therapy,transjugular intrahepatic portosystemic shunt(TIPS)is effective and safe.Shunting blood by TIPS diverts portal blood to the systemic circulation,potentially increasing systemic blood volume and benefiting renal function.However,TIPS could also divert nitric oxide to the systemic circulation,potentially worsening systemic hypotension and perfusion,which could be detrimental to renal function.Available evidence indicates that TIPS often improves renal function in patients with portal hypertension,with or without HRS.No studies have shown persistently decreased renal function after TIPS.However,these data are insufficient to support a recommendation for the use of TIPS specifically for HRS.In patients without pre-existing HPS,TIPS does not appear to significantly affect pulmonary gas exchange.Results of TIPS in HPS have been inconsistent;some studies have shown improvement,but effects were transient.No studies have shown a persistent decline in pulmonary function after TIPS.The evidence supports the need for large randomized controlled trials to investigate the beneficial effects of TIPS for HRS.Similar pulmonary function data are less clear regarding TIPS for HPS.The aim of the current report was to review the literature regarding the effects of TIPS on renal and pulmonary function in hepatic decompensation,with or without the development of HRS or HPS.

Focal Nodular Hyperplasia: A Comprehensive Review with a Particular Focus on Pathogenesis and Complications

Focal nodular hyperplasia is a benign tumor of the liver that is often found incidentally with imaging.The purpose of this review is to discuss the pathophysiology,rare complications that can occur due to these lesions,and management options.A literature review was performed on clinical trials and case reports involving focal nodular hyperplasia complications and management of these,as well as the proposed pathogenesis underlying these tumors.Although exposure to oral contraceptive pills and endogenous hormones have been thought to play a role in the development of these lesions,this has not been proven.Most recently,they are thought to arise as a consequence of a vascular anomaly causing alterations in the expression of angiopoietin genes.Complications are rare,but previous cases have reported associated pain,rupture and compression of nearby structures(hepatic vein,stomach,biliary system).Resection of focal nodular hyperplasia is not usually recommended.However,if there is associated pain with no other identifiable cause or presence of a large or growing lesion with risk of causing a complication,then surgical resection,radiofrequency ablation or arterial embolization should be considered.

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.

Novel Approaches to Inhibition of HBsAg Expression from cccDNA and Chromosomal Integrants:A Review

Hepatitis B virus(HBV)is a widely prevalent liver infection that can cause acute or chronic hepatitis.Although current treatment modalities are highly effective in the suppression of viral levels,they cannot eliminate the virus or achieve definitive cure.This is a consequence of the complex nature of HBV-host interactions.Major challenges to achieving sustained viral suppression include the presence of a high viral burden from the HBV DNA and hepatitis B surface antigen(HBsAg),the presence of reservoirs for HBV replication and antigen production,and the HBV-impaired innate and adaptive immune response of the host.Those therapeutic methods include cell entry inhibitors,HBsAg inhibitors,gene editing approaches,immune-targeting therapies and direct inhibitors of covalently closed circular DNA(cccDNA).Novel approaches that target these key mechanisms are now being studied in preclinical and clinical phases.In this review article,we provide a comprehensive review on mechanisms by which HBV escapes elimination from current treatments,and highlight new agents to achieve a definitive HBV cure.

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.

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.