Biomarkers and subtypes of deranged lipid metabolism in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.

Fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals

AIM To determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.METHODS Transient elastography with controlled attenuation parameter(CAP) was used to assess hepatic steatosis post-sustained virological response(SVR);the CAP technology was not available in the United States at study initiation.Liver stiffness/fibrosis was measured before and 47 wk after treatment completion.Patients with genotype 3 and patients with cirrhosis were excluded.RESULTS One hundred and one patients were included in the study.Post-SVR there were decreases from baseline in alanine aminotransferase(ALT)(63.1 to 17.8 U/L),aspartate aminotransferase(51.8 to 21.5 U/L) and fibrosis score(7.4 to 6.1 k Pa)(P < 0.05).Post-SVR,48 patients(47.5%) had steatosis on CAP;of these,6.25% had advanced fibrosis.Patients with steatosis had higher body mass index(29.0 vs 26.1 kg/m2),glucose(107.8 vs 96.6 mg/d L),ALT(20.4 vs 15.3 mg/d L),CAP score(296.3 vs 212.4 d B/m) and fibrosis score(7.0 vs 5.3 k Pa);P < 0.05.Interestingly,compared to baseline,both patients with and without steatosis had change in fibrosis score post-SVR(7.7 k Pa vs 7.0 k Pa and 7.0 k Pa vs 5.3 k Pa);alternatively,(P < 0.05) and therefore patients with steatosis continued to have clinically significant stiffness(≥ 7 k Pa).CONCLUSION Fatty liver is very common in hepatitis C virus(HCV) patients post-SVR.These patients continue to have elevated mean fibrosis score(≥ 7 k Pa) compared to those without fatty liver;some have advanced fibrosis.Long term follow up is needed to assess steatosis and fibrosis in HCV patients post-SVR.

Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review

BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous,intramuscular,or oral forms of AdoMet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of bias.Mean serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following AdoMet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver enzymes.Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk.One of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 wk.The comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk,but not within2 wk.All of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 wk.Of the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized studies.The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk.Of the four studies reporting symptoms of depression,two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk.CONCLUSION Data from both randomized and non-randomized studies suggest that AdoMet improves some biochemical liver parameters and symptoms of cholestasis within 2 wk,with further improvements observed in some studies after 4 and 8 wk of treatment.

Clinical considerations in the management of non-alcoholic steatohepatitis cirrhosis pre- and post-transplant: A multi-system challenge

Non-alcoholic steatohepatitis(NASH)is the most common chronic liver disease worldwide,and the fastest growing indication for liver transplantation in the United States.NASH is now the leading etiology for liver transplantation in women,the second leading indication for men,and the most common cause amongst recipients aged 65 years and older.Patients with end-stage liver disease related to NASH represent a unique and challenging patient population due the high incidence of associated comorbid diseases,including obesity,type 2 diabetes(T2D),and hypertension.These challenges manifest in the pre-liver transplantation period with increased waitlist times and waitlist mortality.Furthermore,these patients carry considerable risk of morbidity and mortality both before after liver transplantation,with high rates of T2D,cardiovascular disease,chronic kidney disease,poor nutrition,and disease recurrence.Successful transplantation for these patients requires identification and management of their comorbidities in the face of liver failure.Multidisciplinary evaluations include a thorough pre-transplant workup with a complete cardiac evaluation,control of diabetes,nutritional support,and even,potentially,consultation with a bariatric surgeon.This article provides a comprehensive review of the conditions and challenges facing patients with NASH cirrhosis undergoing liver transplantation and provides recommendations for evaluation and management to optimize them before liver transplantation to produce successful outcomes.

Characterization of patients with both alcoholic and nonalcoholic fatty liver disease in a large United States cohort

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is the hepatic manifestation of the metabolic syndrome(MetS)and is characterized by steatosis in the absence of significant alcohol consumption.However,MetS and significant alcohol intake coexist in certain individuals which may lead to the development of BAFLD.AIM To assess the clinical characteristics of patients with both alcoholic and NAFLD(BAFLD)in a large cohort in the United States.METHODS Adults from the National Health and Nutrition Examination Survey between 2003-2014 were included.NAFLD was diagnosed based on elevated alanine aminotransferase(ALT)and being overweight or obese in the absence of other liver diseases.BAFLD patients met the criteria for NAFLD but also had either MetS or type 2 diabetes and consumed excessive amounts of alcohol.Univariable and multivariable analysis were performed to assess differences between NAFLD and BAFLD and to compare severity based on a validated fibrosis score(FIB4 index).RESULTS The prevalence of NAFLD was at 25.9%(95%CI;25.1-26.8)and that of BAFLD was 0.84%(0.67,1.02)which corresponds to an estimated 1.24 million Americans affected by BAFLD.Compared to NAFLD,patients with BAFLD were more likely to be male,smokers,have higher ALT,aspartate aminotransferase,triglycerides,and lower platelets;P<0.01 for all.More importantly,after adjusting for MetS components,BAFLD patients were significantly more likely to have advanced fibrosis[adjusted OR(95%CI)based on FIB4 index>2.67 was 3.2(1.4,7.0),P=0.004].CONCLUSION A significant percentage of the American general population is afflicted by BAFLD and these patients tend to have more advanced liver fibrosis.

Simple diagnostic algorithm identifying at-risk nonalcoholic fatty liver disease patients needing specialty referral within the United States

BACKGROUND There is an urgent need to risk stratify patients with suspected nonalcoholic fatty liver disease(NAFLD)and identify those with fibrotic nonalcoholic steatohepatitis.This study aims to apply a simple diagnostic algorithm to identify subjects with at-risk NAFLD in the general population.AIM To apply a simple diagnostic algorithm to identify subjects with at-risk NAFLD in the general population.METHODS Adult subjects were included from the National Health and Nutrition Examination Survey database(2017-2018)if they had elevated alanine aminotransferase(ALT)and excluded if they had evidence of viral hepatitis or significant alcohol consumption.A fibrosis-4(FIB4)cutoff of 1.3 differentiated patients with low risk vs high risk disease.If patients had FIB4>1.3,a FAST score<0.35 ruled out advanced fibrosis.Patients with FAST>0.35 were referred to a specialist.The same algorithm was applied to subjects with type 2 diabetes mellitus(T2DM).RESULTS Three thousand six hundred and sixty-nine patients were identified who met all inclusion and exclusion criteria.From this cohort,911(28.6%)patients had elevated ALT of which 236(22.9%)patients had elevated FIB4 scores≥1.3.Among patients with elevated FIB4 score,75(24.4%)had elevated FAST scores,ruling in advanced fibrosis.This accounts for 2.0%of the overall study population.Applying this algorithm to 737 patients with T2DM,213(35.4%)patients had elevated ALT,85(37.9%)had elevated FIB4,and 42(46.1%)had elevated FAST scores.This accounts for 5.7%of the population with T2DM.CONCLUSION The application of this algorithm to identify at-risk NAFLD patients in need for specialty care is feasible and demonstrates that the vast majority of patients do not need subspecialty referral for NAFLD.

Foregut bypass vs.restrictive bariatric procedures for nonalcoholic fatty liver disease:a meta-analysis of 3,355 individuals

Background:Bariatric surgery represents an important treatment option for severely obese patients with nonalcoholic fatty liver disease(NAFLD).However,there remains inadequate data regarding the effects of different bariatric procedures on various NAFLD parameters,especially for histological outcomes.Thus,this meta-analysis aimed to compare the effects of restrictive bariatric procedures and foregut bypass on the metabolic,biochemical,and histological parameters for patients with NAFLD.Methods:Medline and Embase were searched for articles relating to bariatric procedures and NAFLD.Pairwise meta-analysis was conducted to compare efficacy of bariatric procedures pre-vs.post-procedure with subgroup analysis to further compare restrictive against foregut bypass procedures.Results:Thirty-one articles involving 3,355 patients who underwent restrictive bariatric procedures(n=1,460)and foregut bypass(n=1,895)were included.Both foregut bypass(P<0.01)and restrictive procedures(P=0.03)significantly increased odds of fibrosis resolution.Compared to restrictive procedures,foregut bypass resulted in a borderline non-significant decrease in fibrosis score(P=0.06)and significantly lower steatosis score(P<0.001).For metabolic parameters,foregut bypass significantly lowered body mass index(P=0.003)and low-density lipoprotein(P=0.008)compared to restrictive procedures.No significant differences were observed between both procedures for aspartate aminotransferase(P=0.17)and alkaline phosphatase(P=0.61).However,foregut bypass resulted in significantly lower gamma-glutamyl transferase than restrictive procedures(P=0.01)while restrictive procedures resulted in significantly lower alanine transaminase than foregut bypass(P=0.02).Conclusions:The significant histological and metabolic advantages and comparable improvements in biochemical outcomes support the choice of foregut bypass over restrictive bariatric procedures in NAFLD management.

A Class Effect Network Meta-analysis of Lipid Modulation in Non-alcoholic Steatohepatitis for Dyslipidemia

Background and Aims:Pharmaceutical therapy for NASH is associated with lipid modulation,but the consensus on drug treatment is limited and lacks comparative analysis of effectiveness.A network meta-analysis was conducted to compare NASH drug classes in lipid modulation.Methods:Online databases were searched for randomized controlled trails(RCTs)evaluating NASH treatments in biopsy-proven NASH patients.Treatments were classified into four groups:(1)inflammation,(2)energy,(3)bile acids,and(4)fibro-sis based on the mechanism of action.A Bayesian network analysis was conducted with outcome measured by mean difference(MD)with credible intervals(Crl)and surface un-der the cumulative ranking curve(SUCRA).Results:Forty-four RCTs were included in the analysis.Bile acid modulat-ing treatments(MD:0.05,Crl:0.03-0.07)were the best treatment for improvement in high-density lipid(HDL)cho-lesterol,followed by treatments modulating energy(MD:0.03,Crl:0.02-0.04)and fibrosis(MD:0.01,Crl:−0.12 to 0.14)compared with placebo.The top three treatments for reduction in triglycerides were treatments modulating energy(MD:−0.46,Crl:−0.49 to−0.43),bile acids(MD:−0.22,Crl:−0.35 to−0.09),and inflammation(MD:−0.08,Crl:−0.13 to−0.03)compared with placebo.SUCRA found treatment modulating fibrosis(MD:−1.27,Crl:−1.76 to−0.79)was the best treatment for reduction in low-density lipid(LDL)cholesterol followed by treatment modulating in-flammation(MD:−1.03,Crl:−1.09 to−0.97)and energy(MD:−0.37,Crl:−0.39 to−0.34)compared with placebo,but LDL cholesterol was worsened by treatments modulat-ing bile acids.Conclusions:Network analysis comparing the class effects of dyslipidemia modulation in NASH found that treatment targets can include optimization of athero-genic dyslipidemia.Future studies are required to evaluate the cardiovascular outcomes.

Hepatocellular carcinoma surveillance in nonalcoholic fatty liver disease patients

INTRODUCTION.Non-alcoholic fatty liver disease(NAFLD)is the leading cause of chronic liver disease worldwide and is an umbrella term for liver disease encompassing non-alcoholic steatohepatitis(NASH),advanced fibrosis,cirrhosis,and/or hepatocellular carcinoma(HCC)[1].The burden of NAFLD is rapidly mounting alongside rising rates of metabolic syndrome and obesity,and NAFLD is projected to become the leading cause of HCC in the United States[2].Among the NAFLD’s global burden,HCC surveillance in patients with NAFLD is challenging given the drawbacks of specific screening modalities and the well-recognized potential for HCC development in those without cirrhosis and even in those with lean NAFLD[3].