Diabetes Mellitus Predicts Occurrence of Cirrhosis and Hepatocellular Cancer in Alcoholic Liver and Non-alcoholic Fatty Liver Diseases

Background and Aims:Alcohol abuse and nonalcoholic fatty liver disease (NAFLD) are common causes of liver disease.Diabetes mellitus (DM) is a common comorbidity among NAFLD patients.We performed this study with the specific aim to examine the impact of DM on progression of alcoholic liver disease (ALD) liver and NAFLD.Methods:Medical charts of 480 patients with ALD or NAFLD (2004-2011) managed at a tertiary center were retrospectively reviewed.NAFLD was diagnosed based on exclusion of other causes of liver disease and alcohol use of <10 g/d.ALD was diagnosed based on alcohol use of >40 g/d in women or >60 g/d in men for >5years.Results:Of 480 patients (307 NAFLD),200 diabetics differed from nondiabetics for:age (52±11 vs.49±11 years;p=0.004);male gender (48% vs.57%;p=0.03);metabolic syndrome (49% vs.30%;p=0.0002);NAFLD (80% vs.56%;p<0.0001);cirrhosis (70% vs.59%;p=0.005);and hepatocellular carcinoma (HCC;8% vs.3%;p=0.009).Over a 3 year median follow-up period,diabetics relative to nondiabetics had a higher probability to develop cirrhosis (60% vs.41%;p=0.022) and HCC (27% vs.10%;p=0.045).There was a trend for increased development of hepatic encephalopathy in diabetics compared to nondiabetics (55% vs.39%;p=0.053),and there was no difference between the two groups in survival or other liver disease complications.Conclusions:DM increased risk for cirrhosis and HCC among patients with ALD and NAFLD.Prospective studies with longer follow-up periods are needed to examine the impact of DM on survival and the role of aggressive HCC screening in diabetic cirrhotics.

Acute Kidney Injury in Patients with Cirrhosis

Acute kidney injury (AKI) occurs commonly in patients with advanced cirrhosis and negatively impacts pre-and posttransplant outcomes.Physiologic changes that occur in patients with decompensated cirrhosis with ascites,place these patients at high risk of AKI.The most common causes of AKI in cirrhosis include prerenal injury,acute tubular necrosis (ATN),and the hepatorenal syndrome (HRS),accounting for more than 80% of AKI in this population.Distinguishing between these causes is particularly important for prognostication and treatment.Treatment of Type 1 HRS with vasoconstrictors and albumin improves short term survival and renal function in some patients while awaiting liver transplantation.Patients with HRS who fail to respond to medical therapy or those with severe renal failure of other etiology may require renal replacement therapy.Simultaneous liver kidney transplant (SLK) is needed in many of these patients to improve their post-transplant outcomes.However,the criteria to select patients who would benefit from SLK transplantation are based on consensus and lack strong evidence to support them.In this regard,novel serum and/or urinary biomarkers such as neutrophil gelatinase-associated lipocalin,interleukins-6 and 18,kidney injury molecule-1,fatty acid binding protein,and endothelin-1 are emerging with a potential for accurately differentiating common causes of AKI.Prospective studies are needed on the use of these biomarkers to predict accurately renal function recovery after liver transplantation alone in order to optimize personalized use of SLK.

Incidence, Mortality and Predictors of Acute Kidney Injury in Patients with Cirrhosis:A Systematic Review and Meta-analysis

Background and Aims:Acute kidney injury(AKI)is com-mon in patients with cirrhosis but the incidence is heteroge-neous among studies.We performed a meta-analysis to describe the incidence of AKI and its impact on patient mor-tality in patients with cirrhosis.We also evaluated the admis-sion variables predicting development of AKI.Methods:A systematic search of various databases was performed up to November 2018.Meta-analyses were performed using ran-dom effects models.Results:Of 18,474 patients with cirrho-sis from 30 selected studies,5,648 developed AKI,with a pooled incidence of 29%(95% confidence interval[CI]:28-30%,I2 of 99%).In-hospital mortality assessed in eight stud-ies was six-fold higher among AKI patients,as compared to those without AKI(odds ratio[OR]6.72,95%CI:3.47-13,p<0.0001,I2 of 70%).Three studies on patients admitted to intensive care showed about six-fold higher mortality among AKI patients(OR 5.90,95%CI:3.21-10.85,p>0.0001).Mor-tality remained significantly high,at days 30 and 90 and even at 1-year follow up after development of AKI.Of 12 admission variables analyzed,model for end-stage liver disease score,Child-Pugh-Turcotte stage C,presence of ascites,and pres-ence of sepsis/septic shock were statistically significant risk factors for AKI.Conclusions:AKI occurred in about 29% of patients with cirrhosis and is associated with a six-fold in-creased risk of in-hospital mortality.Mortality remained high even in long-term follow-up of 1 year.Patients at risk for AKI development can be recognized at admission.Prospective studies are needed to develop strategies for improving out-come of these patients.

PNPLA3 as a Genetic Determinant of Risk for and Severity of Non-alcoholic Fatty Liver Disease Spectrum

Background and Aims:Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD).We performed a systematic review and meta-analysis to examine the association of PNPLA3 polymorphisms with the spectrum and severity of this disease.Methods:Studies evaluating the association between the PNPLA3 polymorphism spectrum (fatty liver,steatohepatitis,cirrhosis,and hepatocellular carcinoma) and NAFLD were included.Pooled data are reported as odds ratios (ORs) with 95% confidence intervals.Results:Of 393 potentially relevant studies,35 on NAFLD were included in the analysis.Compared to healthy controls,the pooled ORs for rs738409 CG and GG compared to CC among patients with non-alcoholic fatty liver (NAFL)were 1.46 (1.16-1.85) and 2.76 (2.30-3.13),and were 1.75 (1.24-2.46) and 4.44 (2.92-6.76) among patients with non-alcoholic steatohepatitis respectively.The respective ORs for CG and GG compared to the CC genotype were 2.35 (0.90-6.13) and 5.05 (1.47-17.29) when comparing nonalcoholic hepatocellular carcinoma to NAFL patients.Among the NAFLD patients,the ORs for G allele frequency when comparing steatosis grade 2-3 to grade 0-1 NAFL,when comparing the NAFLD activity score of ≥ 4 to score ≤ 3,when comparing NASH to NAFLD,when comparing the presence of lobular inflammation to absence,and when comparing the presence of hepatocyte ballooning to absence were 2.33 (1.43-3.80),1.80 (1.36-2.37),1.66 (1.42-1.94),1.58 (1.19-2.10),and 2.63 (1.87-3.69) respectively.Subgroup analysis based on ethnicity showed similar results.Conclusions:PNPLA3 polymorphisms have strong association with the risk for and severity of NAFLDs.PNPLA3 polymorphism plays an evolving role in diagnosis and treatment decisions in patients with NAFLD.

Management of Hepatorenal Syndrome:A Review

Acute kidney injury (AKI) occurs frequently in patients with cirrhosis, and hepatorenal syndrome (HRS) is second most common etiology of AKI after volume responsible pre-renal etiology. AKI in these patients negatively impacts pre- and post-transplant patient survival and healthcare burden. Re-duced effective blood volume with consequent reduced renal blood flow, along with systemic inflammation in patients with decompensated cirrhosis, result in susceptibility to HRS. In this article, we will review updates over the last 5 years on the changing definition with diagnostic criteria and nomenclature of AKI and HRS, data on medical treatment with vasocon-strictors, and urinary biomarkers in diagnosis of etiology of AKI. We will also discuss the significance of liver trans-plantation evaluation once the diagnosis of HRS is established and the post-transplant immunosuppression management. We will also review one of the challenging issues that remains among transplant-eligible patients, that of allocation of si-multaneous liver kidney transplant. Finally, we will review the new implemented policy from the Organ Procurement Trans-plant Network on simultaneous liver kidney allocation.

Severe Alcoholic Hepatitis:Atypical Presentation with Markedly Elevated Alkaline Phosphatase

Alcoholic hepatitis(AH)is an acute inflammatory liver disease with poor prognosis.Infections in AH are difficult to detect and contribute to short-term mortality.Intrahepatic cholestasis and elevated alkaline phosphatase levels are also associated with worse outcomes.This report describes an uncommon presentation of severe AH.

Integrated Multidisciplinary Management of Alcoholassociated Liver Disease

Alcohol-associated liver disease(ALD)is one of the most common liver diseases and indications for liver transplantation(LT).Alcohol use disorder(AUD),a frequent accompaniment in ALD patients,may also be associated with psychiatric comorbidities such as depression and anxiety.Identification of ALD at an earlier stage,and treatment of AUD may help prevent progression to advanced stage of ALD such as cirrhosis and alcoholic hepatitis.Screening for alcohol use and AUD treatment in ALD patients is often not performed due to several barriers at the level of patients,clinicians,and administrative levels.This review details the integrated multidisciplinary care model especially on the specific role of the hepatologist,psychiatrist,addiction counselor,and social worker in providing complete management for the dual pathology of liver disease and of AUD.Laboratory assessment,pharmacological and behavioral therapies,and recommended assessments for follow-up care by the respective specialists is outlined.We provide perspective along with the literature support,with the goal of providing team based comprehensive care of patients with ALD.

Racial and Health Disparities among Cirrhosis-related Hospitalizations in the USA

Background and Aims:Alcohol-associated liver disease(ALD)is the most common cause of advanced liver disease worldwide,including in the USA.Alcohol use and cirrhosis mortality is higher in American Indian/Alaska Native(AI/AN)compared to Whites.Data are scanty on ALD as a liver disease etiology in AI/AN compared to other races and ethnicities.Methods:The National Inpatient Sample on 199,748 cirrhosis-related hospitalizations,14,241(2,893 AI/AN,2,893 Whites,2,882 Blacks,2,879 Hispanics,and 2,694 Asians or other races)matched 1:1 for race/ethnicity on demographics,insurance,and income quartile of the residence zip code analyzed.Results:After controlling for geographic location and hospital type,odds ratio(OR)and 95%confidence interval(CI)for ALD as cirrhosis etiology was higher among admissions in AI/AN vs.Whites[1.55(1.37–1.75)],vs.Blacks[1.87(1.65–2.11)],vs.Hispanic[1.89(1.68–2.13)]and Asians/other races[2.24(1.98–2.53)].OR was also higher for AI/AN vs.all other races for alcohol-associated hepatitis(AH)as one of the discharge diagnoses.The findings were similar in a subgroup of 4,649 admissions with decompensated cirrhosis and in a cohort of 350 admissions with acute-on-chronic liver failure as defined by EASL-CLIF criteria.Alcohol use disorder diagnosis was present in 38%of admissions in AI/AN vs.24–30%in other races,p<0.001.A total of 838(5.9%)admissions were associated with in-hospital mortality.OR(95%CI)for in-hospital mortality in AI/AN individuals was 34%reduced vs.Blacks[0.66(0.51–0.84)],but no difference was observed on comparison with other races.Conclusions:ALD,including AH,is the most common etiology among cirrhosisrelated hospitalizations in the USA among AI/AN individuals.In-hospital mortality was observed in about 6%of admissions,which was higher for Blacks and similar in other races compared to admissions for AI/AN.Public health policies should be implemented to reduce the burden of advanced ALD among AI/AN individuals.

Impact of COVID-19 on Liver Transplant Activity in the USA: Variation by Etiology and Cirrhosis Complications

Background and Aims:The COVID-19 pandemic has impacted the care of patients with liver disease.We examined impact of COVID-19 on liver transplant(LT)activity in the USA.Methods:LT listings in the United Network for Organ Sharing(UNOS)database(April 2018–May 2021)were analyzed to examine the impact of COVID-19 pandemic on the LT activity based on etiology:hepatitis C virus(HCV),alcohol-associated liver disease(ALD),alcoholic hepatitis(AH),and nonalcoholic steatohepatitis(NASH)complications:hepatocellular carcinoma(HCC)and acute-on-chronic liver failure(ACLF)grade 2 or 3 and Model for End-Stage Liver Disease(MELD)score.Joinpoint regression models assessed time trend changes on a log scale.Results:Of 23,871 recipients(8,995 in the COVID era,April 2018–February 2020),mean age 52 years,62% men,61% Caucasian,32%ALD,15%HCC,30%ACLF grades 2–3,and mean MELD score 20.5,monthly LT changes were a decrease of 3.4%for overall LTs and 22%for HCC after September 2020,and increase of 4.5%for ALD since 11/2020 and 17%since 03/2021 for ACLF grade 2–3.Monthly MELD scores increased by 0.7 and 0.36 after June 2020 for HCV and HCC respectively.Conclusions:The COVID-19 pandemic has impacted LT activity,with a decrease of LTs especially for HCC,and an increase of LTs for ALD and severe ACLF.Strategies are needed to reorganize cirrhosis patients to overcome the aftereffects of COVID-19 pandemic.

Mitochondrial dysfunction and alcohol-associated liver disease:a novel pathway and therapeutic target

In a recent study in signal transduction and targeted therapy,Zhou et al.provided novel experimental data on the role of DNAdependent protein kinase catalytic subunit(DNA-PKcs)in causing abnormalities in the structure and function of mitochondria of hepatocytes,leading to liver injury and alcohol-associated liver disease(ALD).

Ammonia level at admission predicts in-hospital mortality for patients with alcoholic hepatitis

Objective.Alcoholic hepatitis(AH),a unique clinical syndrome among patients with chronic and active alcohol use,is associated with high short-term mortality.An elevated ammonia level is associated with mortality in patients with acute liver failure;however,its impact in AH has not been well-studied.Methods.A retrospective study was performed on patients admitted to a tertiary-care hospital with the discharge diagnosis of AH.Patients meeting criteria for AH were included in the final data analysis.Multivariate logistic regression models were built to examine the impact of serum ammonia in predicting in-hospital mortality(IHM)and 30-day mortality(TDM).Subgroup analysis was also performed,which was limited to patients who had hepatic encephalopathy.Results.Of the 105 AH patients included,26(25%)died during the initial hospitalization.Among the 79 patients who survived initial hospitalization,30(39%)died within 30 days.Information about ammonia levels at admission was available for 82 patients.Of these,25 patients had IHM and significantly higher ammonia level(97 vs.69 lmol/L,P<0.01).Among the 57 who survived hospitalization,ammonia levels were not significantly different(71 vs.67 lmol/L,P=0.69)in patients with and without TDM.The addition of ammonia to the multivariate regression models including age,sex,cirrhosis,treatment and model for end-stage liver disease(MELD)score improved the C statistics for IHM from 0.708 to 0.801 and for TDM from 0.756 to 0.766,respectively.These results were identical,even when limited to patients with hepatic encephalopathy.Conclusion.AH patients with elevated ammonia levels at admission have higher IHM;however,they do not seem to play a significant role in 30-day mortality for patients who survived hospitalization.

Sending an SOS: Healing the Liver with the Bone Marrow

Citation of this article:Ayares G,Arab JP,Singal AK.Sending an SOS:Healing the Liver with the Bone Marrow.J Clin Transl Hepatol 2022;10(1):1-3.doi:10.14218/JCTH.2021.00557.Cirrhosis,an end stage of any chronic liver disease is a form of impaired regeneration leading to progressive dif-fuse hepatic fibrosis.The healthcare burden of cirrhosis is increasing,and it is currently the 13th leading cause of death globally.The progression of liver injury and fibrosis results in portal hypertension and hepatic insufficiency.

Changing Population of Liver Transplant Recipients in the Era of Direct-acting Antiviral Therapy

Background and Aims:With the availability of direct-acting antiviral(DAA)therapy for hepatitis C virus(HCV)infection and changing liver disease etiology for liver transplantation(LT),data on the changes in LT recipient population in the DAA era are scanty.Methods:The United Network for Organ Sharing(UNOS)registry(01/2007 to 06/2018)was used to develop a retrospective cohort of LT recipients for HCV,alcohol-associated liver disease(ALD),and non-alcoholic steatohepatitis(NASH).LT recipients in the DAA era(2013-2018)were compared with those in the pre-DAA era(2007-2012)era for recipient characteristics.Chi-square and analysis of variance were the statistical tests used for categorical and continuous variables,respectively.Results:Of 40,309 LT recipients(21,110 HCV,7586 NASH,and 11,713 ALD),the 21,790 in the DAA era(9432 HCV,7240 ALD,and 5118 NASH)were more likely to be older,female,obese,diabetic,have acute-on-chronic liver failure with a higher model for end-stage liver disease score,receive grafts with a lower donor risk index,and have waited on the LT list for a shorter period compared with their pre-DAA era counterparts.Specific to ALD,LT recipients with alcohol hepatitis were more likely to be younger at the time of LT.Of 9895 LT recipients with hepatocellular carcinoma,recipients in the DAA era were observed to have a higher proportion of HCV(43%vs.32%,p<0.001),a lower proportion of ALD(9%vs.12%,p<0.001),and no change for NASH(13%vs.13%,p=0.9)compared with the pre-DAA era.Within the hepatocellular carcinoma population,LT recipients in the DAA era were older,diabetic,and waited on the LT list longer compared with their pre-DAA counterparts.Conclusions:Along with changing liver disease etiology in the DAA era,the LT recipient population demographics,comorbidities,liver disease severity,and graft quality are changing.These changes are relevant for future studies,immunosuppression,and post-transplant follow-up.