Trends of autoimmune liver disease inpatient hospitalization and mortality from 2011 to 2017:A United States nationwide analysis

BACKGROUND Autoimmune liver diseases(AiLD)encompass a variety of disorders that target either the liver cells(autoimmune hepatitis,AIH)or the bile ducts[primary biliary cholangitis(PBC),and primary sclerosing cholangitis(PSC)].These conditions can progress to chronic liver disease(CLD),which is characterized by fibrosis,cirrhosis,and hepatocellular carcinoma.Recent studies have indicated a rise in hospitalizations and associated costs for CLD in the US,but information regarding inpatient admissions specifically for AiLD remains limited.AIM To examine the trends and mortality of inpatient hospitalization of AiLD from 2011 to 2017.METHODS This study is a retrospective analysis utilizing the National Inpatient Sample(NIS)databases.All subjects admitted between 2011 and 2017 with a diagnosis of AiLD(AIH,PBC,PSC)were identified using the International Classification of Diseases(ICD-9)and ICD-10 codes.primary AiLD admission was defined if the first admission code was one of the AiLD codes.secondary AiLD admission was defined as having the AiLD diagnosis anywhere in the admission diagnosis(25 diagnoses).Subjects aged 21 years and older were included.The national estimates of hospitalization were derived using sample weights provided by NIS.χ^(2)tests for categorical data were used.The primary trend characteristics were in-hospital mortality,hospital charges,and length of stay.RESULTS From 2011 to 2017,hospitalization rates witnessed a significant decline,dropping from 83263 admissions to 74850 admissions(P<0.05).The patients hospitalized were predominantly elderly(median 53%for age>65),mostly female(median 59%)(P<0.05),and primarily Caucasians(median 68%)(P<0.05).Medicare was the major insurance(median 56%),followed by private payer(median 27%)(P<0.05).The South was the top geographical distribution for these admissions(median 33%)(P<0.05),with most admissions taking place in big teaching institutions(median 63%)(P<0.05).Total charges for admissions rose from 66031 in 2011 to 78987 in 2017(P<0.05),while the inpatient mortality rate had a median of 4.9%(P<0.05),rising from 4.67%in 2011 to 5.43%in 2017.The median length of stay remained relatively stable,changing from 6.94 days(SD=0.07)in 2011 to 6.51 days(SD=0.06)in 2017(P<0.05).Acute renal failure emerged as the most common risk factor associated with an increased death rate,affecting nearly 68%of patients(P<0.05).CONCLUSION AiLD-inpatient hospitalization showed a decrease in overall trends over the studied years,however there is a significant increase in financial burden on healthcare with increasing in-hospital costs along with increase in mortality of hospitalized patient with AiLD.

Hepatocellular carcinoma:A comprehensive review

Hepatocellular carcinoma(HCC) is rapidly becoming one of the most prevalent cancers worldwide. With a rising rate, it is a prominent source of mortality. Patients with advanced fibrosis, predominantly cirrhosis and hepatitis B are predisposed to developing HCC. Individuals withchronic hepatitis B and C infections are most commonly afflicted. Different therapeutic options, including liver resection, transplantation, systemic and local therapy, must be tailored to each patient. Liver transplantation offers leading results to achieve a cure. The Milan criteria is acknowledged as the model to classify the individuals that meet requirements to undergo transplantation. Mean survival remains suboptimal because of long waiting times and limited donor organ resources. Recent debates involve expansion of these criteria to create options for patients with HCC to increase overall survival.

Efficacy and safety of anti-hepatic fibrosis drugs

Recent progress in our understanding of the pathways linked to progression from hepatic insult to cirrhosis has led to numerous novel therapies being investigated as potential cures and inhibitors of hepatic fibrogenesis. Liver cirrhosis is the final result of prolonged fibrosis, which is an intimate balance between fibrogenesis and fibrinolysis. A number of these complex mechanisms are shared across the various etiologies of liver disease. Thankfully, investigation has yielded some promising results in regard to reversal of fibrosis, particularly the indirect benefits associated with antiviral therapy for the treatment of hepatitis B and C and the farnesoid receptor agonist for the treatment of primary biliary cholangitis and metabolic associated fatty liver disease. A majority of current clinical research is focused on targeting metabolic associated fatty liver disease and its progression to metabolic steatohepatitis and ultimately cirrhosis, with some hope of potential standardized therapeutics in the near future. With our ever-evolving understanding of the underlying pathophysiology, these therapeutics focus on either controlling the primary disease(the initial trigger of fibrogenesis), interrupting receptor ligand interactions and other intracellular communications, inhibiting fibrogenesis, or even promoting resolution of fibrosis. It is imperative to thoroughly test these potential therapies with the rigorous standards of clinical therapeutic trials in order to ensure the highest standards of patient safety. In this article we will briefly review the key pathophysiological pathways that lead to liver fibrosis and present current clinical and experimental evidence that has shown reversibility of liver fibrosis and cirrhosis, while commenting on therapeutic safety.

Liver injury induced by paracetamol and challenges associated with intentional and unintentional use

Drug induced liver injury(DILI)is a common cause of acute liver injury.Paracetamol,also known as acetaminophen,is a widely used anti-pyretic that has long been established to cause liver toxicity once above therapeutic levels.Hepatotoxicity from paracetamol overdose,whether intentional or nonintentional,is the most common cause of DILI in the United States and remains a global issue.Given the increased prevalence of combination medications in the form of pain relievers and antihistamines,paracetamol can be difficult to identify and remains a significant cause of acute hepatotoxicity,as evidenced by its contribution to over half of all acute liver failure cases in the United States.This is especially concerning given that,when co-ingested with other medications,the rise in serum paracetamol levels may be delayed past the 4-hour post-ingestion mark that is currently used to determine patients that require medical therapy.This review serves to describe the clinical and pathophysiologic features of hepatotoxicity secondary to paracetamol and provide an update on current available knowledge and treatment options.

Emerging concepts in alcoholic hepatitis

Severe alcoholic hepatitis is implicated as a costly,worldwide public health issue with high morbidity and mortality. The one-month survival for severe alcoholic hepatitis is low with mortality rates high as 30%-50%. Abstinence from alcohol is the recommended firstline treatment. Although corticosteroids remain as the current evidence based option for selected patients with discriminant function > 32, improvement of short-term survival rate may be the only benefit. Identification of individuals with risk factors for the development of severe alcoholic hepatitis may provide insight to the diverse clinical spectrum and prognosis of the disease. The understanding of the complex pathophysiologic processes of alcoholic hepatitis is the key to elucidating new therapeutic treatments. Newer research describes the use of gut microbiota modification, immune modulation, stimulation of liver regeneration, caspase inhibitors, farnesoid X receptors, and the extracorporeal liver assist device to aid in hepatocellular recovery. Liver transplantation can be considered as the last medical option for patients failing conventional medical interventions. Although the preliminary data is promising in patients with low risk of recividism, controversy remains due to organ scarcity. This review article comprehensively summarizes the epidemiology, pathophysiology, risk factors, and prognostic indicators of severe alcoholic hepatitis with a focus on the current and emerging therapeutics.

Immunobiology of hepatocarcinogenesis: Ways to go or almost there?

Hepatocellular carcinoma is on the rise and occurs in the setting of chronic liver disease and cirrhosis.Though treatment modalities are available,mortality from this cancer remains high.Medical therapy with the utilization of biologic compounds such as the Food and Drug Administration approved sorafenib might be the only option that can increase survival.Immunotherapy,with modern pharmacologic developments,is a new frontier in cancer therapy and therefore the immunobiology of hepatocarcinogenesis is under investigation.This review will discuss current concepts of immunobiology in hepatocarcinogenesis along with current treatment modalities employing immunotherapy.The tumor microenvironment along with a variety of immune cells coexists and interplays to lead to tumorigenesis.Tumor infiltrating lymphocytes including CD8+ T cells,CD4+ T cells along with regulatory T cells,tumor associated macrophages,tumor associated neutrophils,myeloid derived suppressor cells,and natural killer cells interact to actively provide anti-tumor or pro-tumor effects.Furthermore,oncogenic pathways such as Raf/mitogenactivated protein kinase/extracellular-signal-regulated kinase pathway,phosphatidyl-3-kinase/AKT/mammalian target or rapamycin,Wnt/β-catenin,nuclear factor-κB and signal transducers and activators of transcription 3 may lead to activation and proliferation of tumor cells and are also considered cornerstones in tumorigenesis.Immunotherapy directed at this complex milieu of cells has been showned to be successful in cancer treatment.The use of vaccines,adoptive cell therapy and immune checkpoint inhibitor modulation are current options for therapy.Further translational research will shed light to concepts such as anti-tumor immunity which can add another alternative in the therapeutic armamentarium.

Cellular based treatment modalities for unresectable hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common primary malignancy of the liver and is unfortunately associated with an overall poor prognosis and high mortality.Early and intermediate stages of HCC allow for treatment with surgical resection,ablation and even liver transplantation,however disease progression warrants conventional systemic therapy.For years treatment options were limited to molecular-targeting medications,of which sorafenib remains the standard of care.The recent development and success of immune checkpoint inhibitors has proven to be a breakthrough in the treatment of HCC,but there is an urgent need for the development of further novel therapeutic treatments that prolong overall survival and minimize recurrence.Current investigation is focused on adoptive cell therapy including chimeric antigen receptor-T cells(CAR-T cells),T cell receptor(TCR)engineered T cells,dendritic cells,natural killer cells,and tumor infiltrating lymphocyte cells,which have shown remarkable success in the treatment of hematological and solid tumor malignancies.In this review we briefly introduce readers to the currently approved systemic treatment options and present clinical and experimental evidence of HCC immunotherapeutic treatments that will hopefully one day allow for revolutionary change in the treatment modalities used for unresectable HCC.We also provide an up-to-date compilation of ongoing clinical trials investigating CAR-T cells,TCR engineered T cells,cancer vaccines and oncolytic viruses,while discussing strategies that can help overcome commonly faced challenges when utilizing cellular based treatments.

Hepatitis E in immunocompromised individuals

Hepatitis E virus(HEV)originally identified as a cause of acute icteric hepatitis in developing countries has grown to be a cause of zoonotic viral hepatitis in developed countries such as the United States.While there are eight identified genotypes to date,genotype 1(HEV1),HEV2,HEV3,HEV4 are the most common to infect humans.HEV1 and HEV2 are most common in developing countries including Latina America,Africa and Asia,and are commonly transmitted through contaminated water supplies leading to regional outbreaks.In contrast HEV3 and HEV4 circulate freely in many mammalian animals and can lead to occasional transmission to humans through fecal contamination or consumption of undercooked meat.The incidence and prevalence of HEV in the United States is undetermined given the absence of FDA approved serological assays and the lack of commercially available testing.In majority of cases,HEV infection is a selflimiting hepatitis requiring only symptomatic treatment.However,this is not the case in immunocompromised individuals,including those that have undergone solid organ or stem cell transplantation.In this subset of patients,chronic infection can be life threatening as hepatic insult can lead to inflammation and fibrosis with subsequent cirrhosis and death.The need for re-transplantation as a result of post-transplant hepatitis is of great concern.In addition,there have been many reported incidents of extrahepatic manifestations,for which the exact mechanisms remain to be elucidated.The cornerstone of treatment in immunocompromised solid organ transplant recipients is reduction of immunosuppressive therapies,while attempting to minimize the risk of organ rejection.Subsequent treatment options include ribavirin,and pegylated interferon alpha in those who have demonstrated ribavirin resistance.Further investigation assessing safety and efficacy of anti-viral therapy is imperative given the rising global health burden.Given this concern,vaccination has been approved in China with other investigations underway throughout the world.In this review we introduce the epidemiology,diagnosis,clinical manifestations,and treatment of HEV,with emphasis on immunocompromised individuals in the United States.

New Year’s greeting and overview of World Journal of Hepatology in 2021

The World Journal of Hepatology(WJH)was launched in October 2009.It mainly publishes articles reporting research findings in the field of hepatology,covering a wide range of topics,including viral hepatitis B and C,non-alcoholic fatty liver disease,alcoholic liver disease,autoimmune and chronic cholestatic liver disease,drug-induced liver injury,cirrhosis,liver failure,hepatocellular carcinoma,coronavirus disease 2019-related liver conditions,etc.As of December 31,2020,the WJH has published 1349 articles,among which,the total cites is 18995 and the average cites per article is 14.In celebrating the New Year,we are pleased to share with you special a New Year’s greeting from the WJH Editors-in-Chief,along with a detailed overview of the journal’s submission,peer review and publishing metrics from 2020.In all,we are appreciative for the substantive support and submissions from authors worldwide,and the dedicated efforts and expertise provided by our invited reviewers and editorial board members.

Hospital teaching status on the outcomes of patients with esophageal variceal bleeding in the United States

BACKGROUND Acute variceal bleeding is a major complication of portal hypertension and is a leading cause of death in patients with cirrhosis.There is limited data on the outcomes of patients with esophageal variceal bleeding in teaching versus nonteaching hospitals.Because esophageal variceal bleeding requires complex management,it may be hypothesized that teaching hospitals have lower mortality.AIM To assess the differences in mortality,hospital length of stay(LOS)and cost of admission for patients admitted for variceal bleed in teaching versus nonteaching hospitals across the US.METHODS The National Inpatient Sample is the largest all-payer inpatient database consisting of approximately 20%of all inpatient admissions to nonfederal hospitals in the United States.We collected data from the years 2008 to 2014.Cases of variceal bleeding were identified using the International Classification of Diseases,Ninth Edition,Clinical Modification codes.Differences in mortality,LOS and cost were evaluated for patients with esophageal variceal bleed between teaching and nonteaching hospitals and adjusted for patient characteristics and comorbidities.RESULTS Between 2008 and 2014,there were 58362 cases of esophageal variceal bleeding identified.Compared with teaching hospitals,mortality was lower in nonteaching hospitals(8.0%vs 5.3%,P<0.001).Median LOS was shorter in nonteaching hospitals as compared to teaching hospitals(4 d vs 5 d,P<0.001).A higher proportion of non-white patients were managed in teaching hospitals.As far as procedures in nonteaching vs teaching hospitals,portosystemic shunt insertion(3.1%vs 6.9%,P<0.001)and balloon tamponade(0.6%vs 1.2%)were done more often in teaching hospitals while blood transfusions(64.2%vs 59.9%,P=0.001)were given more in nonteaching hospitals.Using binary logistic regression models and adjusting for baseline patient demographics and comorbid conditions the mortality,LOS and cost in teaching hospitals remained higher.CONCLUSION In patients admitted for esophageal variceal bleeding,mortality,length of stay and cost were higher in teaching hospitals versus nonteaching hospitals when controlling for other confounding factors.

Expanding indications for liver transplantation in the era of liver transplant oncology

Despite numerous advances and emerging data,liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications.In an era of persistent organ shortage and increasing organ demand,allocation of liver grafts must be considered carefully.While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation,tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes.As more studies seeking to expand the oncologic indications for liver transplantation are emerging,it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes.In addition,time from diagnosis to transplantation appears to correlate with survival,as stable disease over time portends better outcomes post-operatively.Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques.While tumor size and stage are important prognostic predictors for most malignancies,patient and tumor selection protocols are necessary.As the fields of medical and surgical oncology continue to evolve,it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively.Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms.Current data evaluating liver transplantation for expanded oncologic indications such as:expanded criteria hepatocellular carcinoma,intrahepatic cholangiocarcinoma,mixed tumors,and liver limited metastatic colorectal carcinomas,incorporate multi-modal therapies and evaluation of tumor treatment response.While further investigation is necessary,initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology.

Trends in hospitalization for alcoholic hepatitis from 2011 to 2017:A USA nationwide study

BACKGROUND Severe alcoholic hepatitis(AH)is one of the most lethal manifestations of alcoholassociated liver disease.In light of the increase in alcohol consumption worldwide,the incidence of AH is on the rise,and data examining the trends of AH admission is needed.AIM To examine inpatient admission trends secondary to AH,along with their clinical outcomes and epidemiological characteristics.METHODS The National Inpatient Sample(NIS)database was utilized,and data from 2011 to 2017 were reviewed.We included individuals aged≥21 years who were admitted with a primary or secondary diagnosis of AH using the International Classification of Diseases(ICD)-9 and its correspondent ICD-10 codes.Hepatitis not related to alcohol was excluded.The national estimates of inpatient admissions were obtained using sample weights provided by the NIS.RESULTS AH-related hospitalization demonstrated a significant increase in the USA from 281506(0.7%of the total admission in 2011)to 324050(0.9%of the total admi-ssion in 2017).The median age was 54 years.The most common age group was 45–65 years(range 57.8%–60.7%).The most common race was white(63.2%–66.4%),and patients were predominantly male(69.7%–71.2%).The primary healthcare payers were Medicare(29.4%–30.7%)and Medicaid(21.5%–32.5%).The most common geographical location was the Southern USA(33.6%–34.4%).Most patients were admitted to a tertiary care center(50.2%–62.3%)located in urban areas.Mortality of AH in this inpatient sample was 5.3%in 2011 and 5.5%in 2017.The most common mortality-associated risk factors were acute renal failure(59.6%–72.1%)and gastrointestinal hemorrhage(17.2%–20.3%).The total charges were noted to range between$25242.62 and$34874.50.CONCLUSION The number of AH inpatient hospitalizations significantly increased from 2011 to 2017.This could have a substantial financial impact with increasing healthcare costs and utilization.AH-mortality remained the same.

De novo and recurrence of metabolic dysfunction-associated fatty liver disease after liver transplantation

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a new acronym adopted from the consensus of international experts.Given the increasing prevalence of MAFLD in pre-transplant settings,de novo and recurrent graft steatosis/MAFLD are common in post-transplant settings.The impact of graft steatosis on long-term outcomes is unclear.The current knowledge of incidence rate,risk factors,diagnosis,long-term outcomes,and management of graft steatosis(both de novo and recurrent)is discussed in this review.

Nonalcoholic fatty liver disease is associated with worse intestinal complications in patients hospitalized for Clostridioides difficile infection

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)has become the leading cause of chronic liver disease with increasing prevalence worldwide.Clostridioides difficile infection(CDI)remains the most common cause of nosocomial diarrhea in developed countries.AIM To assess the impact of NAFLD on the outcomes of hospitalized patients with CDI.METHODS This study was a retrospective cohort study.The Nationwide Inpatient Sample database was used to identify a total of 7239 adults admitted as inpatients with a primary diagnosis of CDI and coexisting NAFLD diagnosis from 2010 to 2014 using ICD-9 codes.Patients with CDI and coexisting NAFLD were compared to those with CDI and coexisting alcoholic liver disease(ALD)and viral liver disease(VLD),individually.Primary outcomes included mortality,length of stay,and total hospitalization charges.Secondary outcomes were in-hospital complications.Multivariate regression was used for outcome analysis after adjusting for possible confounders.RESULTS CDI with NAFLD was independently associated with lower rates of acute respiratory failure(2.7%vs 4.2%,P<0.01;2.7%vs 4.2%,P<0.05),shorter length of stay(days)(5.75±0.16 vs 6.77±0.15,P<0.001;5.75±0.16 vs 6.84±0.23,P<0.001),and lower hospitalization charges(dollars)(38150.34±1757.01 vs 46326.72±1809.82,P<0.001;38150.34±1757.01 vs 44641.74±1660.66,P<0.001)when compared to CDI with VLD and CDI with ALD,respectively.CDI with NAFLD was associated with a lower rate of acute kidney injury(13.0%vs 17.2%,P<0.01),but a higher rate of intestinal perforation(P<0.01)when compared to VLD.A lower rate of mortality(0.8%vs 2.7%,P<0.05)but a higher rate of intestinal obstruction(4.6%vs 2.2%,P=0.001)was also observed when comparing CDI with NAFLD to ALD.CONCLUSION Hospitalized CDI patients with NAFLD had more intestinal complications compared to CDI patients with VLD and ALD.Gut microbiota dysbiosis may contribute to the pathogenesis of intestinal complications.

Acetaminophen-Induced Hepatotoxicity:a Comprehensive Update

Hepatic injury and subsequent hepatic failure due to both intentional and non-intentional overdose of acetaminophen (APAP) has affected patients for decades,and involves the cornerstone metabolic pathways which take place in the microsomes within hepatocytes.APAP hepatotoxicity remains a global issue;in the United States,in particular,it accounts for more than 50% of overdose-related acute liver failure and approximately 20% of the liver transplant cases.The pathophysiology,disease course and management of acute liver failure secondary to APAP toxicity remain to be precisely elucidated,and adverse patient outcomes with increased morbidity and mortality continue to occur.Although APAP hepatotoxicity follows a predictable timeline of hepatic failure,its clinical presentation might vary.N-acetylcysteine (NAC) therapy is considered as the mainstay therapy,but liver transplantation might represent a life-saving procedure for selected patients.Future research focus in this field may benefit from shifting towards obtaining antidotal knowledge at the molecular level,with focus on the underlying molecular signaling pathways.

Characteristics and Inpatient Outcomes of Primary Biliary Cholangitis and Autoimmune Hepatitis Overlap Syndrome

Background and Aims:Primary biliary cholangitis(PBC)and autoimmune hepatitis(AIH)are hepatobiliary diseases of presumed immune-mediated origin that have been shown to overlap.The aim of this retrospective trial was to use national data to examine the characteristics and outcomes of patients hospitalized with overlapping PBC and AIH(PBC/AIH).Methods:The National Inpatient Sample was used to identify hospitalized adult patients with PBC,AIH,and PBC/AIH from 2010 to 2014 by International Classification of Diseases-Ninth Edition Revision codes;patients with hepatitis B virus and hepatitis C virus infection were excluded.Primary outcomes measures were in-hospital outcomes that included mortality,respiratory failure,septic shock,length of stay,and total hospital charges.Secondary outcomes were the clinical characteristics of PBC/AIH,including the comorbid extrahepatic autoimmune disease pattern and complications of cirrhosis.Results:A total of 3,478 patients with PBC/AIH were included in the study.PBC/AIH was associated with higher rates of Sjögren’s syndrome(p<0.001;p<0.001),lower rates of Crohn’s disease(p<0.05;p<0.05),and higher rates of cirrhosis-related complications when compared to PBC or AIH alone.There were similar rates of mortality between the PBC/AIH,PBC,and AIH groups.The PBC/AIH group had higher rates of septic shock when compared to the PBC group(p<0.05)and AIH group(p<0.05)after adjusting for possible confounders.Conclusions:PBC/AIH is associated with a lower rate of Crohn’s disease,a higher rate of Sjögren’s syndrome,higher rates of cirrhosis-related complications,and significantly increased risk of septic shock compared to PBC and AIH individually.

Vitamin D Is Associated with Severity and Mortality of Non-alcoholic Fatty Liver Disease: A US Population-based Study

Background and Aims:There has been increasing evidence that vitamin D deficiency may increase the risk of metabolic syndrome.Since metabolic syndrome is a major risk factor for non-alcoholic fatty liver disease (NAFLD),we aimed to investigate the association between vitamin D and the severity and mortality of NAFLD.Methods:Data was obtained from the United States Third National Health and Nutrition Examination Survey conducted in 1988-1994,with followup mortality data through 2011.NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases and categorized as normal,mild,moderate or severe.The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS).ANOVA (F-test) was used to evaluate the association between vitamin D level and degree of NAFLD,and Cox proportional hazards regression analysis was used for survival analyses.Results:Vitamin D levels for normal,mild,moderate and severe steatosis were 25.1 ± 0.29 ng/mL,24.7 ± 0.42 ng/mL,23.7 ± 0.37 ng/mL and 23.6 ± 0.60 ng/mL,respectively (trend p < 0.001).Likewise,vitamin D levels for low,intermediate and high NFS categories were 24.7 ± 0.38 ng/mL,23.4 ± 0.42 ng/mL and 21.5 ± 0.57 ng/mL,respectively (trend p < 0.001).After median-follow up over 19 years,vitamin D deficiency was significantly associated with diabetes-and Alzheimer's diseaserelated mortality (hazard ratio (HR):3.64,95%CI:1.51-8.82 and HR:4.80,95%CI:1.53-15.1,respectively),with a borderline significance in overall mortality (HR:1.16,95%CI:0.99-1.36,p =0.06).Conclusion:Vitamin D level was inversely related to the degree of liver steatosis and fibrosis.Moreover,vitamin D deficiency was associated with diabetes-and Alzheimer's disease-related mortality in NAFLD patients.

Fatty Liver Disease and Gut Microbiota:A Comprehensive Update

Nonalcoholic fatty liver disease(NAFLD)is the accumulation of fat in the liver in the absence of secondary causes.NAFLD is a multifactorial disease that results from the interaction of genetic predisposition and metabolic,inflammatory and environmental factors.Among these factors,dysregulation of gut microbiome has been linked to the development of fatty liver disease.The microbiome composition can be modified by dietary habits leading to gut microbiome dysbiosis,especially when a diet is rich in saturated fats,animal products and fructose sugars.Different species of bacteria in the gut metabolize nutrients differently,triggering different pathways that contribute to the accumulation of fat within the liver and triggering inflammatory cascades that promote liver damage.In this review,we summarize the current understanding of the roles of gut microbiota in mediating NAFLD development and discuss possible gut microbiota-targeted therapies for NAFLD.We summarize experimental and clinical evidence,and draw conclusions on the therapeutic potential of manipulating gut microbiota to decrease the incidence and prevalence of fatty liver disease.

Cardiac Syndromes in Liver Disease:A Clinical Conundrum

Understanding the interaction between the heart and liver is pivotal for managing patients in whom both organs are affected.Studies have shown that cardio-hepatic interactions are bidirectional and that their identification,assessment,and treatment remain challenging.Congestive hepatopathy is a condition that develops in the setting of long-standing systemic venous congestion.If left untreated,congestive hepatopathy may lead to hepatic fibrosis.Acute cardiogenic liver injury develops as a combination of venous stasis and sudden arterial hypoperfusion due to cardiac,circulatory,or pulmonary failure.The treatment of both conditions should be directed toward optimizing the cardiac substrate.Hyperdynamic syndrome may develop in patients with advanced liver disease and lead to multiorgan failure.Cirrhotic cardiomyopathy or abnormalities in pulmonary vasculature,such as hepatopulmonary syndrome and portopulmonary hypertension may also develop.Each complication has unique treatment challenges and implications for liver transplantation.The presence of atrial fibrillation and atherosclerosis in liver disease brings another layer of complexity,particularly in terms of anticoagulation and statin use.This article provides an overview of cardiac syndromes in liver disease,focusing on current treatment options and future perspectives.

Improved Outcomes Following Hepatocellular Carcinoma(HCC)Diagnosis in Patients Screened for HCC in a Large Academic Liver Center versus Patients Identified in the Community

Background and Aims:Hepatocellularcarcinoma(HCC)isthe sixth most commonly occurring cancer worldwide.Knowledge and adherence to HCC surveillance guidelines has been associated with earlier detection.We sought to evaluate characteristics and outcomes following HCC diagnosis in patients screened for HCC in a large academic liver center versus patients diagnosed and referred from the community.Methods:We reviewed the records of patients diagnosed with HCC in the liver center of an academic institution from January 1999 till December 2013.Patients were classified into two groups:patients followed in our hepatology clinic and patients with HCC recently referred to our center.Univariate analysis was performed using chi-squared test and multivariate analysis was performed using SPSS 22.0.Results:The records of 410 patients were reviewed,and included 77.3%of patients referred from the community and 22.7%of patients followed in our clinic.In the clinic group,75.6%were identified with one nodule at initial diagnosis,compared to 65.6%in the referral group.Patients in the referral group were more likely to present with tumors≥5 cm at diagnosis,with 28.7%compared to 5.4%in the clinic group(P<0.0001).Patients referred from the community were also less likely to undergo transplant,with 32.2%as compared to 48.4%of the clinic group(P<0.004).Conclusion:Patients with chronic liver disease managed in an academic liver center present in the early stage of HCC diagnosis and are more likely to meet the Milan criteria and undergo transplant.Early referral to a specialized transplant center,if feasible,where a multidisciplinary approach is utilized might be essential in the management of chronic liver disease.