An update on non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Asia

Introduction: Non-alcoholic fatty liver disease (NAFLD) has become the most overwhelming liver disease in Asia. In consideration of its increasing medical and economic impact on Asian people, it is time for us to review the update data in Asian countries and formulate strategies to cope with this emerging health problem in Asia. Moreover, growing data indicates that NAFLD may be a systemic disease, not just confined to liver-specific morbidity and mortality, but also associated with several extra-hepatic manifestations, such as cardiovascular diseases, chronic renal diseases, and malignancy. As the co-occurrence of NAFLD and viral hepatitis is common in Asia, issues related to the impact of NAFLD on the clinical outcomes and management of viral hepatitis remain to be elucidated.

Areas covered: In this article, a narrative review was conducted, searching for literature from PubMed, Ovid MEDLINE, and the Cochrane Library database till August 2016. Studies relevant to the emerging data of NAFLD in Asia, including the diagnosis, risk factors, the assessment and management of Asian NAFLD patients were examined and discussed.

Expert commentary: Collaboration in Asian countries to develop an effective and practical measurement to assess the severity of NAFLD is urgently required.     

Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH): treatment

Non-alcoholic fatty liver disease is now recognized as a cause of potentially progressive liver damage, posing patients at risk of advanced liver failure. Unfortunately, the natural history of disease is only partly known, the disease is slowly progressive and therapeutic outcomes are difficult to define. These factors have limited therapeutic trials to pilot studies, and very few randomized-controlled studies are available. The concept that insulin-resistance, coupled with oxidative stress, may be the underlying mechanism responsible for fat accumulation and disease progression points to insulin-sensitizing agents (metformin, thiazolidinediones) as the most promising drugs. They proved effective in reducing enzyme levels in the short period, but very limited information is available on liver histology, not to say progression to liver cell failure. Large, long-term, placebo-controlled randomized studies are eagerly awaited. Outside controlled studies, nutritional counselling and physical exercise aimed at moderate weight loss remain the basis of any therapeutic intervention.     

Efficacy of statins in treatment and development of non-alcoholic fatty liver disease and steatohepatitis: A systematic review and meta-analysis

BackgroundNon-Alcoholic Fatty Liver Disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. There is no universally accepted effective treatment for NAFLD. Although various studies propose statins effective in lowering liver enzymes and in improving liver histology, their potency in the treatment and development of NAFLD remains unknown.PurposeWe conducted this meta-analysis to evaluate the efficacy of statins in the treatment and the development of NAFLD.MethodsElectronic databases (MEDLINE and Cochrane CENTRAL) were searched from their inception until May 2021 for observational studies and randomized controlled trials (RCTs) that assessed the efficacy of statins for the treatment of NAFLD and its development. Studies were included irrespective of the dosage or duration, and their risk of bias was assessed. The outcomes of interest for our study were the effect of statins on liver histology (steatosis, fibrosis and necroinflammation, NAFLD activity score [NAS]) and liver enzymes (Alanine transaminase [ALT], Aspartate transaminase [AST], and Gamma-glutamyl transferase [GGT] levels). To pool continuous outcomes, a random-effects model was used to derive weighted mean difference (WMD) or standardized mean difference (SMD) and their corresponding 95% confidence intervals (CIs). Generic inverse variance was then used for different measurement units reported by the studies. For studies investigating the effects of statins on the development of NAFLD, generic inverse variance along with random effects model was used to derive odds ratio (ORs) and its corresponding 95% confidence interval (CI).ResultsA total of 14 studies including 1,247,503 participants were short-listed for our analysis. All the studies included in our analysis had a low to moderate risk of bias. The results of our analysis suggest that statins may significantly reduce the risk of developing NAFLD (OR:0.69, 95% CI [0.57,0.84]; p = 0.0002; I² =36%). Statin use significantly reduced ALT levels (WMD: -27.28, 95% CI [-43.06, -11.51]; p = 0.0007; I² =90%), AST levels (WMD: -10.99, 95% CI [-18.17, -3.81]; p = 0.003; I² =79%) and GGT levels (WMD: -23.40, 95% CI [-31.82, -14.98]; p < 0.00001; I² = 21%) in patients presenting with NAFLD at baseline. In liver histology outcomes, steatosis grade (SMD: -2.59, 95% CI [-4.61, -0.56]; p = 0.01; I² = 95%), NAS (WMD: -1.03, 95% CI [-1.33, -0.74]; p < 0.00001; I² = 33%), necro-inflammatory stage (WMD: -0.19, 95% CI [-0.26, -0.13]; p < 0.00001; I² = 0%) and significant fibrosis (OR:0.20, 95% CI [0.04, 0.95]; p = 0.04; I² = 97%) underwent notable reduction. However, fibrosis stage outcome (WMD: 0.07, 95% CI [-0.05, 0.20]; p = 0.27; I² = 0%) was non-significant.ConclusionThere was a significant decrease in transaminase and transferase levels. Marked improvement in liver histology of NAFLD patients was observed. Statin use also remarkably reduced the risk of developing NAFLD. Future large-scale trials can further aid in identifying the positive impact of statins in treatment for NAFLD and those at risk of developing it.     

吡格列酮对非酒精性脂肪肝的疗效观察

目的寻找一安全有效的治疗非酒精性脂肪性肝病的方法。方法将非酒精性脂肪性肝病患者43例随机分组,吡格列酮组22例(n=22),对照组21例(n=21),比较两组疗效(观察ALT,GGT,TG,HOMA-IR,BMI等指标)。结果3个月时,两组的观察指标均有改善,虽治疗组更明显,但无显著差异(P>0.05),6个月时,ALT,GGT,TG,HOMA-IR及疗效,治疗组与对比组比较,疗效有显著差异(19/22,11/21,P<0.05)。结论胰岛素增敏剂(吡格列酮)治疗NAFLD,安全、有效,值得临床推广应用。     

Correlation between Fibroscan and laboratory tests in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis patients for assessing liver fibrosis

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is a spectrum of disease ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), through to advanced fibrosis and cirrhosis. Many patients with NAFLD remain undiagnosed and recognizing those at risk is very crucial. Although liver biopsy is the gold standard method for diagnosing and staging NAFLD, non-invasive imaging and lab modalities are also very promising in diagnosing these diseases.AIMTo explore some of these non-invasive modalities in this context and assess how they hold up in terms of making a diagnosis while avoiding an invasive procedure like a liver biopsy.METHODSThis study was conducted on NAFLD/NASH patients (n = 73) who underwent Fibroscan examinations at Saint George Hospital University Medical Center over 17 mo in order to assess liver fibrosis. Obtained Fibroscan results were correlated to laboratory tests and calculated aspartate transaminase (AST)/alanine transaminase (ALT) ratio, AST platelet ratio index (APRI) score and Fibrosis-4 score.RESULTSA significant age difference was observed across fibrosis stages of investigated patients. The mean stiffness score was 9.48 ± 11.77 KPa. A significant negative correlation was observed between ALT, AST, Albumin, gamma-glutamyl transferase, cholesterol, LDL, HDL, triglycerides, and ALP when compared across fibrosis stages. On the other hand, a significant positive correlation was found between Bilirubin, PT INR, partial thromboplastin time, glucose, and Platelet count when compared across fibrosis stages, in addition to AST/ALT ratio, APRI, and Fib-4 scores.CONCLUSIONThis study showed that Ultrasound alone is not efficient in the assessment of advancement of liver disease. Furthermore, the high positive relation between AST/ALT ratio, APRI and Fib-4 scores with fibrosis stages in NAFLD patients suggests that they could be used clinically in combination with Fibroscan to predict significant fibrosis and cirrhosis and to avoid liver biopsy.     

非酒精性脂肪肝患者肝脏脂肪含量与心血管病危险因素的关系

目的:探讨非酒精性脂肪肝(NAFLD)患者肝脏脂肪含量(LFC)与心血管病危险因素及聚集数目的关系。方法:选择1021例体检者为研究对象,超声诊断NAFLD患者283例为NAFLD组;另以非NAFLD体检者738例为非NAFLD组,采用超声定量检测患者的LFC,分析不同心血管病危险因素及聚集数目对NAFLD患病率及其LFC的影响。结果:在与NAFLD发生相关的心血管病危险因素中,OR值高到低为高TG、糖尿病、中心性肥胖、混合型高脂血症、高胆固醇血症、非中心性肥胖(OR分别为2.13,2.11,1.95,1.91,1.78,1.74,P均0.05)。NAFLD组患者LFC为(15.56±4.46)%,多元线性回归分析显示BMI、WHR、TC、TG与NAFLD患者LFC相关(β=0.411,0.437,0.335,0.478,t=2.812,2.986,2.321,2.215,P0.05)。1021例研究对象,0~4个心血管危险因素者分别244例(23.9%)、358例(35.1%)、288例(28.2%)、89例(8.7%)、42例(4.1%),NAFLD的患病率分别为7.8%、16.2%、37.5%、73.0%、78.6%,(χ~2趋势=23.934,P0.05)。NAFLD患者0~4个心血管危险因素者的LFC分别为(10.92±2.19)%,(13.23±3.21)%,(15.34±4.29)%,(18.13±5.32)%,(19.36±5.39)%,差异有统计学意义(F=18.293,P0.05),NAFLD患者的LFC与心血管病危险因素聚集数目呈正相关(r=0.327,P0.05)。结论:心血管病危险因素与NAFLD密切相关,心血管病危险因素聚集可增加NAFLD患病率和LFC。     

Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease.

While the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome will have steatosis, only a minority will ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis. For ALD, the dose and pattern of alcohol intake, along with obesity are the most important environmental factors determining disease risk. For NAFLD, dietary saturated fat and antioxidant intake and small bowel bacterial overgrowth may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the alcohol dehydrogenases and aldehyde dehydrogenase alcohol metabolising genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, TNF-alpha, transforming growth factor-beta, and angiotensinogen may be associated with steatohepatitis and/or fibrosis.     

Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH): diagnosis and clinical course

Non-alcoholic fatty liver disease (NAFLD) is a frequent syndrome encompassing fatty liver alone and steatohepatitis (NASH). Often asymptomatic, the suspicion arises because of abnormal aminotransferases or a bright liver on abdominal ultrasound. It should be suspected during evaluation of associated conditions as obesity, diabetes or dyslipidaemia. The diagnostic evaluation must exclude other potential causes of liver disease and may include a liver biopsy, the only method able to confirm features of necroinflammation and fibrosis that define NASH and its prognostic implications. Indeed, the presence of necroinflammation has been associated with a significant risk of progression to cirrhosis and eventually hepatocellular carcinoma. Age >45 years, obesity and diabetes have also been associated with an increased risk of liver fibrosis and progression to cirrhosis. Given the high prevalence of NAFLD, general measures of life-style changes, focusing on exercise, diet, and total alcohol abstinence, should be implemented before a liver biopsy is considered.     

奥贝胆酸治疗非酒精性脂肪肝的疗效和机制——胆汁酸药物的利和弊

［摘要］　非酒精性脂肪肝（NAFLD）是世界上发病率最高的肝病,但是目前无批准上市治疗NAFLD的药物。近年来,NAFLD被认为是代谢相关性脂肪肝病,其发病机制与胆汁酸代谢的改变有关。奥贝胆酸是一种半合成的胆汁酸,同时也是一种强效且具有高选择性的法尼醇X受体（FXR）激动剂和脂肪酸转运蛋白5（FATP5）的强效抑制剂。目前,与高剂量熊去氧胆酸（UDCA）和其他胆汁酸药物治疗NAFLD相比,小剂量奥贝胆酸在治疗NAFLD中具有更多的优势和探索价值。     

Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disorder in Western countries, with a prevalence of 20-30%. NAFLD comprises 'silent liver disease', in which simple steatosis is the only histological finding and which is benign in course, and nonalcoholic steatohepatitis, which is characterized by hepatocellular injury and inflammation with or without fibrosis. NAFLD is clinically important, because even benign fatty liver can progress to steatohepatitis in many patients, which can lead to liver cirrhosis and its complications and hepatocellular carcinoma. NAFLD is a hepatic manifestation of metabolic syndrome; it is closely related to other clinical features of metabolic syndrome, and thus to cardiovascular morbidity. There are several different noninvasive techniques for formal diagnosis and follow-up, but liver biopsy remains the gold standard. The most important therapeutic strategies include lifestyle changes, including changes in dietary habits aimed at weight loss and blood pressure regulation, with a consequent decrease in insulin resistance. For some patients with NAFLD/nonalcoholic steatohepatitis, pharmacological treatment is the best option, although further studies are needed to confirm its efficacy and tolerability.     

二甲双胍联合吡格列酮治疗非酒精性脂肪性肝病合并2型糖尿病患者疗效研究

目的 探讨应用二甲双胍联合吡格列酮治疗非酒精性脂肪性肝病(NAFLD)合并2型糖尿病(T2DM)患者的效果。方法 2018年10月～2020年10月我院收治的NAFLD合并T2DM患者86例,采用随机数字表法分为对照组43例和观察组43例,分别给予二甲双胍或二甲双胍联合吡格列酮治疗24 w。常规检测谷丙转氨酶(ALT)、谷草转氨酶(AST)、谷氨酰转肽酶(GGT)、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)、空腹血糖(FPG)、糖化血红蛋白(HbA1c);采用电化学发光法检测血清空腹胰岛素(FINS),并计算稳态模型胰岛素抵抗指数(HOMA-IR)。结果 在治疗24 w末,观察组血清AST水平为(37.9±4.2)U/L,显著低于对照组【(50.7±3.8)U/L,P<0.05】,GGT水平为(64.1±6.2)U/L,显著低于对照组【(73.1±7.0)U/L,P<0.05】;FPG水平为(6.0±1.2)mmol/L,显著低于对照组【(6.8±1.5)mmol/L,P<0.05】,HbA1c水平为(7.2±1.1)%...     

Abdominal obesity,chronic inflammation and the risk of non-alcoholic fatty liver disease

Introduction and ObjectivesThe purpose of this study was to evaluate the effect of abdominal obesity and chronic inflammation on risk of non-alcoholic fatty liver disease (NAFLD) among Chinese population.Materials and MethodsOverall, 50776 staff from the Kailuan Group who participated in and finished physical examinations between 2006 and 2007 were included in the cohort study. Their medical information was collected and they were followed after examination. The correlations of waist-to-height ratio (WHtR) or serum high-sensitivity C-reactive protein (hs-crp) with NAFLD were analyzed. Then, we categorized all participants into four groups: non-abdominal obesity and non-chronic inflammation group, abdominal obesity and non-chronic inflammation group, non-abdominal obesity and chronic inflammation group, abdominal obesity and chronic inflammation group, and non-abdominal obesity and non-chronic inflammation group was used as a control group. The combined effects of abdominal obesity and chronic inflammation with NAFLD were analyzed using the Cox proportional hazard regression model.ResultsAfter a mean follow-up of 5.59±1.79 years, a total of 15451 NAFLD cases occurred. We found the WHtR and hs-crp increase the risk for NAFLD, respectively. Compared with the non-abdominal obesity and non-chronic inflammation group, the risk of NAFLD was significantly increased in the abdominal obesity and non-chronic inflammation group (HR 1.21, 95%CI 1.11-1.32), non-abdominal obesity and chronic inflammation group (HR 1.32, 95%CI 1.27-1.38), abdominal obesity and chronic inflammation group (HR 1.60, 95% CI 1.52-1.70). And, a significant interaction effect was found of abdominal obesity and chronic inflammation on NAFLD.ConclusionsIn this study, it was demonstrated in the Chinese population that both abdominal obesity and chronic inflammation increase the risk of NAFLD, and there is an interaction between the two factors in the incidence of NAFLD.     

Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk

Nonalcoholic fatty liver disease(NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use.The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes.A more advanced form of NAFLD,nonalcoholic steatohepatitis,includes inflammation and liver cell injury,progressive to cryptogenic cirrhosis.NAFLD has become the most common cause of chronic liver disease in children and adolescents.The recent rise in the prevalence rates of overweig...     

Risk of cardiovascular,cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)has emerged as a public health problem of epidemic proportions worldwide.Accumulating clinical and epidemiological evidence indicates that NAFLD is not only associated with liver-related morbidity and mortality but also with an increased risk of coronary heart disease(CHD),abnormalities of cardiac function and structure(e.g.,left ventricular dysfunction and hypertrophy,and heart failure),valvular heart disease(e.g.,aortic valve sclerosis)and arrhythmias(e.g.,atrial fibrillation).Experimental evidence suggests that NAFLD itself,especially in its more severe forms,exacerbates systemic/hepatic insulin resistance,causes atherogenic dyslipidemia,and releases a variety of pro-inflammatory,pro-coagulant and pro-fibrogenic mediators that may play important roles in the pathophysiology of cardiac and arrhythmic complications.Collectively,these findings suggest that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions to decrease the risk for CHD and other cardiac/arrhythmic complications.The purpose of this clinical review is to summarize the rapidly expanding body of evidence that supports a strong association between NAFLD and cardiovascular,cardiac and arrhythmic complications,to briefly examine the putative biological mechanisms underlying this association,and to discuss some of the current treatment options that may influence both NAFLD and its related cardiac and arrhythmic complications.     

Psoriasis,non-alcoholic fatty liver disease,and cardiovascular disease:Three different diseases on a unique background

Psoriasis is a chronic inflammatory immune-mediated skin disease, frequently associated with systemic comorbidities. According to recent data, patients with psoriasis show a greater prevalence of metabolic syndrome, which confers a higher cardiovascular risk. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple epidemiological and physio-pathogenetic aspects linking non-alcoholic fatty liver disease, psoriasis, and cardiovascular disease.     

Antidiabetic drugs and non-alcoholic fatty liver disease: A systematic review,meta-analysis and evidence map

BackgroundThe efficacy of antidiabetic agents for the treatment of non-alcoholic fatty liver disease (NAFLD) remains unclear.AimTo conduct a meta-analysis to study the efficacy of pioglitazone and three novel anti-diabetic agents: glucagon-like peptide-1 (GLP-1) agonists, sodium-glucose co-transporter-2 (SGLT2) inhibitors, and dipeptidyl-peptidase-4 (DPP4) inhibitors in treating NAFLD.MethodsOnline databases were searched in May 2020 for randomized clinical trials. Results from random-effects meta-analysis are presented as weighted mean differences (WMDs) or standard mean differences (SMDs) and corresponding 95% confidence intervals (CIs).ResultsTwenty-six studies (n=946 NAFLD patients) were included. Reductions in ALT were seen with all four drugs: pioglitazone (MD -38.41, p<0.001), SGLT2 inhibitors (MD -16.17, p<0.001), GLP-1 agonists (MD -27.98, p=0.04) and DPP-4 inhibitors (MD -7.41, p<0.001). Pioglitazone (SMD -1.01; p<0.001) and GLP-1 agonists (SMD -2.53, p=0.03) also demonstrated significant improvements in liver steatosis. SGLT2 inhibitors (SMD -4.64, p=0.06) and DPP-4 (SMD -2.49, p=0.06) inhibitors trended towards reduced steatosis; however, these results were non-significant.ConclusionPioglitazone demonstrates significant improvements in transaminases and liver histology in both diabetic and non-diabetic NAFLD patients. Early evidence from diabetic NAFLD patients suggests that novel antidiabetics may lead to improvements in liver enzymes and hepatic steatosis, and this should encourage further research into possible utility of these drugs in treating NAFLD.