Validation of genetic variants associated with metabolic dysfunctionassociated fatty liver disease in an ethnic Chinese population

BACKGROUND Genetic factors play an important role in the pathogenesis and development of metabolic dysfunction-associated fatty liver disease(MAFLD).AIM To study the association of single nucleotide polymorphisms(SNPs),previously identified in Western populations,with the risk of MAFLD in a Singapore Chinese population and their interactions with environmental and medical risk factors.METHODS A retrospective case-control study was conducted with 72 MAFLD cases and 72 controls with no hepatic steatosis on computed tomography,magnetic resonance imaging,or controlled attenuation parameter score.Subjects were recruited from two tertiary hospitals.Genetic alleles such as NCAN,GCKR,LYPLAL1,PNPLA3,PPP1R3B,FDFT1,COL13A1,EFCAB4B,PZP,and TM6SF2 were genotyped using the TaqMan®Predesigned SNP Genotyping Assay.RESULTS Weight and body mass index(BMI)were 1.2-times higher in patients(70.6 kg,95%confidence interval[CI]:57.1-84.1 vs 60.8 kg,95%CI:48.5-73.1,P<0.001 and 26.9 kg,95%CI:23-40.8 vs 23.3 kg 95%CI:19-27.6,P<0.001 respectively).The prevalence of diabetes mellitus in patients was 40.3%and 20.8%in controls(P=0.011).Patients had higher mean triglycerides than controls(P<0.001).PNPLA3 GG was more likely to be associated with MAFLD(43.4%CC vs 69.7%GG,P=0.017,and 44.8%CG vs 69.7%GG,P=0.022).In multivariable analysis,hypertriglyceridemia(odds ratio[OR]:2.0495%CI:1.3-3.1,P=0.001),BMI(OR:1.295%CI:1.1-1.4,P<0.001)and PNPLA3 GG(OR:3.495%CI:1.3-9.2,P=0.014)were associated with MAFLD(area under the receiver operating characteristic curve of 0.823).CONCLUSION Among the Chinese population of Singapore,PNPLA3 homozygous GG allele is a strong predictor of MAFLD,whereas LYPLAL1,GCKR,FDFT1,COL13A1,PZP,and TM6SF2 are not significantly associated.Hypertriglyceridemia,high BMI,and PNPLA3 GG are independent predictors of MAFLD.

Alanine aminotransferase is an inadequate surrogate marker for detecting lamivudine resistance

AIM: To investigate the accuracy of serum alanine aminotransferase (ALT) in diagnosing lamivudine resistance and factors that contributed to abnormal serum ALT.METHODS: This was a retrospective study of chronic hepatitis B patients on lamivudine therapy who were followed for 3-mo with liver function tests and hepatitis B virus (HBV) DNA measurement. Lamivudine resistance was defined as HBV DNA ≥ 1 log from nadir on at least 2 occasions, confirmed by genotyping. Serum ALT levels in patients with lamivudine resistance were compared to serum ALT levels in those without lamivudine resistance. RESULTS: There were 111 patients with and 117 without lamivudine resistance. The area under the receiver operating characteristic of serum ALT to diagnose lamivudine resistance was 0.645 ± 0.037. Serum ALT > 42.5 U/L gave the best diagnostic accuracy with sensitivity = 61%, specificity = 60%, positive predictive value = 60%, negative predictive value = 61%, positive likelihood ratio = 1.53 and negative likelihood ratio = 0.65 for predicting lamivudine resistance, missing 39% of resistant patients. Using other serum ALT cutoffs, diagnostic accuracy was lower. By multivariate analysis, baseline abnormal serum ALT was associated with abnormal ALT during resistance (OR = 5.98, P = 0.003), and males were associated with serum ALT flares during resistance (OR = 8.9, P = 0.016). CONCLUSION: Serum ALT is inadequate for diagnosing lamivudine resistance and has implications where viral resistance testing is suboptimal and for reimbursement of rescue therapy.

Boceprevir early-access for advanced-fibrosis/cirrhosis in Asia-pacific hepatitis C virus genotype 1 non-responders/relapsers

AIM:To examined the efficacy and safety of treatment with boceprevir,PEGylated-interferon and ribavirin(PR)in hepatitis C virus genotype 1(HCVGT1) PR treatmentfailures in Asia.METHODS:The Boceprevir Named-Patient Program provided boceprevir to HCVGT1 PR treatment-failures.Participating physicians were invited to contribute data from their patients:baseline characteristics,ontreatment responses,sustained virological response at week 12(SVR12),and safety were collected and analysed.Multivariate analysis was performed to determine predictors of response.RESULTS:150 patients were enrolled from Australia,Malaysia,Singapore and Thailand(Asians = 86,Caucasians = 63).Overall SVR12 was 61%(Asians= 59.3%,Caucasians = 63.5%).SVR12 was higher in relapsers(78%) compared with non-responders(34%).On-treatment responses predicted SVR,with undetectable HCVRNA at week 4,8 and 12 leading to SVR12 s of 100%,87%,and 82%respectively,and detectable HCVRNA at week 4,8 and 12,leading to SVR12 s of 58%,22%and 6%respectively.Asian patients were similar to Caucasian patients with regards to on-treatment responses.Patients with cirrhosis(n= 69) also behaved in the same manner with regards to on-treatment responses.Those with the IL28 B CC genotype(80%) had higher SVRs than those with the CT/TT(56%) genotype(P = 0.010).Multivariate analysis showed that TW8 and TW12 responses were independent predictors of SVR.Serious adverse events occurred in 18.6%:sepsis(2%),decompensation(2.7%) and blood transfusion(14%).Discontinuations occurred in 30.7%,with 18.6%fulfilling stopping rules.CONCLUSION:Boceprevir can be used successfully in PR treatment failures with a SVR12 > 80%if they have good on-treatment responses;however,discontinuations occurred in 30%because of virological failure or adverse events.

Risk factors for ribavirin treatment failure in Asian organ transplant recipients with chronic hepatitis E infection

BACKGROUND Hepatitis E virus(HEV)infection is a cause of chronic hepatitis in immunosuppressed patients.Sustained virologic response rates to a 12-wk course of ribavirin therapy were reported to be>70%in the West.This study describes the outcome of HEV treatment in a transplant center in Singapore.AIM To study the outcome of ribavirin treatment in a series of chronic HEV patients,and the cause of treatment failure.METHODS We studied all of the transplant recipients who were diagnosed with HEV infection between 2012 to 2015.The outcome of therapy and virologic relapse are monitored for three years after the end of therapy.RESULTS Ten transplant recipients(4 liver,5 kidney,and 1 bone marrow transplantation)with positive HEV RNA were studied.Nine patients received at least 12 wk of ribavirin therapy,and the remaining patient resolved after reducing immunosuppression therapy.Two subjects had prolonged viremia that lasted more than one year,despite continuous ribavirin therapy.Four ribavirin-treated patients(44.4%)had HEV RNA relapse after achieving a virologic response by the end of treatment.The overall failure rate is 66.7%.Being a kidney transplant recipient is the strongest risk factor for not achieving an initial sustained virologic response(0/5 treated,Chi-Square test,P<0.05).The most common side effect of ribavirin is anemia(100%)(haemoglobin reduction of 3-6.2 g/dL).Seven patients required either a blood transfusion or erythropoietin therapy.CONCLUSION The sustained virologic response rate of 12-wk ribavirin therapy for HEV infection in this Asian series was lower than expected.Kidney transplant recipients had a higher rate of treatment failure due to higher immunosuppression requirements and adverse effects.

Emerging liver organoid platforms andtechnologies

Building human organs in a dish has been a long term goal of researchers in pursue of physiologically relevantmodels of human disease and for replacement of worn out and diseased organs. The liver has been an organ ofinterest for its central role in regulating body homeostasis as well as drug metabolism. An accurate liver replicashould contain the multiple cell types found in the organ and these cells should be spatially organized to resembletissue structures. More importantly, the in vitro model should recapitulate cellular and tissue level functions.Progress in cell culture techniques and bioengineering approaches have greatly accelerated the development ofadvance 3-dimensional (3D) cellular models commonly referred to as liver organoids. These 3D models describedrange from single to multiple cell type containing cultures with diverse applications from establishing patientspecificliver cells to modeling of chronic liver diseases and regenerative therapy. Each organoid platform isadvantageous for specific applications and presents its own limitations. This review aims to provide acomprehensive summary of major liver organoid platforms and technologies developed for diverse applications.