Liver-related and extrahepatic events in patients with non-alcoholic fatty liver disease: a retrospective competing risks analysis.
Background & Aim: Non-alcoholic fatty liver disease (NAFLD), and especially fibrotic non-alcoholic steatohepatitis, is associated with high risks of liver-related events (LRE) and extrahepatic events (EHE). We evaluated the competitive risk occurrence of LRE and EHE in a large cohort of biopsy-proven NAFLD stratified according to baseline severity of fibrosis. Methods: Two thousand one hundred thirty-five patients with biopsy-proven NAFLD were enrolled. Observed cumulative incidence functions (CIFs) were used to evaluate the risk of LRE and EHE; cause-specific Cox model and predicted CIFs were fitted to identify predictors of LRE and EHE. A replication cohort of NAFLD patients with live…
IMPACT OF NON-ALCOHOLIC FATTY LIVER DISEASE ON CARDIOVASCULAR RISK IN A GENERAL POPULATION
Background: Background:Nonalcoholic fatty liver (NAFL) is a major cause of liver disease worldwide leading also to a higher risk of cardiovascular events. We aimed to evaluate the impact of fatty liver and fibrosis on cardiovascular risk factors in a general population. Methods: 604 subjects included in the community-based ABCD (Alimentazione, Benessere Cardiovascolare e Diabete) study were recruited. Steatosis (CAP >288 dB/m) and fibrosis (> 8.7 KPa by M and > 7.2 KPa by XL probe) were assessed with FibroScan Cardiovascular risk was evaluated by the Atherosclerotic Cardiovascular Disease (ASCVD) risk estimator and de ned low if <5%, borderline if 5%-7 4%, intermediate if 7-9% a…
Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: Time for reappraisal of BMI-driven approach?
[Objective] The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD.
A Genetic and Metabolic Staging System for Predicting the Outcome of Nonalcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease (NAFLD) is an emerging cause of liver-related events (LREs). Here, we have assessed the ability of a composite score based on clinical features, metabolic comorbidities, and genetic variants to predict LREs. A total of 546 consecutive patients with NAFLD were recruited and stratified according to the fibrosis-4 (FIB-4) index. LREs were defined as occurrence of hepatocellular carcinoma or hepatic decompensation. Cox regression multivariate analysis was used to identify baseline variables associated with LREs. The UK Biobank was used as the validation cohort, and severe liver disease (incidence of cirrhosis, decompensated liver disease, hepatocellular carcinom…
PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD
Background and Aims: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower low-density lipoprotein cholesterol (LDL-C) levels. In this study, we examined the impact of the PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models. Methods: We considered 1874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA…
Noninvasive assessment of liver disease severity in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes
Background: We evaluated the diagnostic accuracy of simple non-invasive tests(NITs) in NAFLD patients with type 2 diabetes(T2D). Methods: This was an individual patient data meta-analysis of 1780 patients with biopsy-proven NAFLD and T2D. The index tests of interest were FIB-4, NAFLD Fibrosis Score(NFS), APRI, liver stiffness measurement(LSM) by vibration-controlled transient elastography(VCTE) and AGILE 3+. The target conditions were advanced fibrosis, nonalcoholic steatohepatitis(NASH) and fibrotic NASH(NASH plus F2-F4 fibrosis). The diagnostic performance of NITs individually or in sequential combination was assessed by area under receiver operating characteristic curve(AUROC) and by dec…
<i>NR1H4</i> rs35724 G&gt;C Variant Modulates Liver Damage in Nonalcoholic Fatty Liver Disease
Background and Aims: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 variant, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis. Methods: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms was genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n=124). Results: The NR1H4 rs35724 variant was protective against severity of steatosis (OR 0.89, 95% C.I.…
A cholestatic pattern predicts major liver-related outcomes in patients with non-alcoholic fatty liver disease
NAFLD patients usually have an increase in AST/ALT levels, but cholestasis can also be observed. We aimed to assess in subjects with NAFLD the impact of the (cholestatic) C pattern on the likelihood of developing major liver-related outcomes (MALO).
PNPLA3 Rs738409 C&gt;G Variant Predicts Liver-Related Outcomes in Patients with Non-Alcoholic Fatty Liver Disease
Background: Patients with NAFLD are at higher risk of developing liver-related complications -liver decompensation(LD) and hepatocellular carcinoma (HCC), including death-. A single nucleotide polymorphism in PNPLA3 gene is associated with a higher prevalence of liver damage and HCC, but prospective date are not available. We aimed to assess whether the common rs738409 variant in PNPLA3 gene can predict the occurrence of liver-related events and death in a large cohort of NAFLD patients. Methods: We considered 471 consecutive Italian individuals with histological diagnosis of NAFLD or clinical diagnosis of compensated NAFLD-related cirrhosis, prospectively followed for at least 6 months. …
RESIST-HCV Criteria to Monitor Progression of Low-Risk Esophageal Varices in Patients With Compensated Cirrhosis After HCV Eradication: The SIMPLE Study: SIMPLE: Scoring Index to Monitor Progression of Low-risk Esophageal varices.
Noninvasive criteria to predict the progression of low-risk esophageal varices (EV) in patients with compensated hepatitis C virus (HCV) cirrhosis after sustained virological response (SVR) by direct-acting antivirals (DAAs) are lacking. Our aim was to assess the diagnostic performance of Rete Sicilia Selezione Terapia-HCV (RESIST-HCV) criteria for EV progression compared with elastography-based criteria (Baveno VI, Expanded Baveno VI, and Baveno VII-HCV criteria).All consecutive patients observed at 3 referral centers with compensated HCV cirrhosis with or without F1 EV who achieved sustained virological response by DAAs were classified at last esophagogastroduodenoscopy (EGDS) as RESIST-H…
Biochemical biomarkers of NAFLD/NASH
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world and the global epidemics of obesity and type 2 diabetes have led to a dramatic increase of its prevalence and incidence. Among NAFLD patients, those with nonalcoholic steatohepatitis (NASH) have a double risk of fibrosis progression, that is the main driver toward the evolution in cirrhosis and its complications, including hepatocellular carcinoma and hepatic decompensation. Furthermore, patients with NAFLD are also at risk for cardiovascular diseases and extrahepatic malignancies, that represent the first and the second cause of death, respectively. The availability of non-invasi…
A Cholestatic Pattern Predicts Liver-Related Events in Patients with Nonalcoholic Fatty Liver Disease
Background & Aims: Liver test alteration patterns can be categorized as: predominantly hepatocellular(H), with an ALT/ALP ratio>5; predominantly cholestatic pattern(C) with a ratio 55 years(HR2.55,95%C.I.1.17-5.54;p=0.01), platelets<150,000/mmc(HR0.14,95%C.I.0.06-0.32;p<0.001), albumin<4g/L(HR0.62,95%C.I.0.35-1.08;p=0.09), C vs M pattern(HR7.86,95%C.I.1.03-60.1;p=0.04), C vs H pattern(HR12.1,95% C.I.1.61-90.9;p=0.01) and fibrosis F3-F4(HR35.8,95%C.I.4.65-275.2;p<0.001) were independent risk factors for LRE occurrence. C vs M pattern(HR14.3,95%C.I.1.90-105.6;p=0.008) and C vs H pattern(HR15.6,95%C.I. 2.10-115.1;p=0.0068) were confirmed independently associated with LRE occurrence in the vali…
Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease.
BACKGROUND & AIMS: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. METHODS: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine amino transferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants wit…
Prevalence and Risk Factors of Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Without Steatohepatitis
In patients with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is a risk factor for the development of fibrosis. However, fibrosis has been observed in livers of patients without NASH. We aimed to estimate the prevalence of fibrosis in patients without NASH and risk factors for fibrosis.We analyzed data from 1738 subjects (44.9% with severe obesity) in a cross-sectional liver biopsy cohort enrolled at referral centers in Italy and Finland. Biopsy specimens were analyzed histologically by a blinded pathologist at each center, and a diagnosis of NASH was made based on steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. We also c…
Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease
Background and aims: Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation is associated with NAFLD severity in individuals with liver biopsy. Methods: We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2889 individuals who underwent liver biopsy for suspected nonalcoholi…
Neurotensin up-regulation is associated with advanced fibrosis and hepatocellular carcinoma in patients with MAFLD
Background & aims: Neurotensin (NTS), a 13-aminoacid peptide localized in central nervous system and gastrointestinal tract, is involved in lipid metabolism and promotes various cancers onset mainly by binding to neurotensin receptor 1 (NTSR1). Increased plasma levels of pro-NTS, the stable NTS precursor, have been associated with type 2 diabetes (T2D), cardiovascular diseases and metabolic associated fatty liver disease (MAFLD). We aimed to evaluate 1) the impact of NTS rs1800832 and NTSR1 rs6090453 genetic variants on liver damage in 1166 MAFLD European individuals, 2) the relation between NTS variant and circulating pro-NTS and 3) the hepatic NTS expression by RNAseq transcriptomic a…
Impact of direct-acting antivirals (DAAs) on cardiovascular diseases in patients with chronic hepatitis C
INTRODUCTION: In the last years the Hepatitis C virus (HCV) infection was a relevant public health problem due to the large number of affected people worldwide and the impact on hepatic and extrahepatic complications. The availability of direct-acting antivirals (DAAs) and the very high rate of sustained virological response (SVR) after treatment has radically changed the course of HCV chronic infection. EVIDENCE ACQUISITION: We searched PubMed for articles published between January 1, 1995, through December 31, 2020, in English language. EVIDENCE SYNTHESIS: Robust evidence showed a close link between HCV infection and development of cardiovascular disease (CVD), as result of the atherogeni…
<i>PCSK9</i> rs11591147 R46L Loss-of-Function Variant Protects Against Liver Damage in Individuals with NAFLD
Background and Aims: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower LDL-C levels. In this study, we examined the impact of PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models. Methods: We considered 1,874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA hepatic expression in human liver, and 2…
Pharmacological Therapy of Non-Alcoholic Fatty Liver Disease: What Drugs Are Available Now and Future Perspectives
The non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease as well as the first cause of liver transplantation. NAFLD is commonly associated with metabolic syndrome (MetS), and this is the most important reason why it is extremely difficult to treat this disease bearing in mind the enormous amount of interrelationships between the liver and other systems in maintaining the metabolic health. The treatment of NAFLD is a key point to prevent NASH progression to advanced fibrosis, to prevent cirrhosis and to prevent the development of its hepatic complications (such as liver decompensation and HCC) and even extrahepatic one. A part of the we…
The Relevance of Noninvasive Tools To Assess Fibrosis in Non-Alcoholic Fatty Liver Disease.
Non-alcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver diseases worldwide, involving about 25% of people. NAFLD incorporates a large spectrum of pathological conditions, from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and its complications include hepatic decompensation and hepatocellular carcinoma (HCC). This progression occurs, over many years, in an asymptomatic way, until advanced fibrosis appears. Thus, the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis are key issues. To date, the histological assessment of fibrosis with liver biopsy is the gold standard, but obviously, invasiveness is the …
AGILE 3+ Score for the Diagnosis of Advanced Fibrosis and for Predicting Liver-related Events in NAFLD.
Background & aims: We aimed to assess the diagnostic accuracy of AGILE 3+, a recently developed score based on the combination of aspartate aminotransferase/alanine aminotransferase ratio, platelet count, diabetes status, sex, age, and liver stiffness measurement (LSM) by transient elastography, when compared with Fibrosis-4 (FIB-4) and LSM, for the diagnosis of advanced fibrosis and for the prediction of liver-related events (LREs) occurrence in patients with NAFLD. Methods: A total of 614 consecutive patients with biopsy-proven NAFLD or clinical diagnosis of NAFLD-related compensated cirrhosis were enrolled. LREs were recorded during follow-up. FIB-4, LSM by transient elastography (Fi…
MAFLD: a multisystem disease
Nonalcoholic fatty liver disease (NAFLD), affecting about 25% of general population and more than 50% of dysmetabolic patients, is an emerging cause of chronic liver disease and its complications. Recently, an international consensus of experts proposed to rename this disease as ‘Metabolic dysfunction-Associated Fatty Liver Disease’ (MAFLD) to focus on the bidirectional interplay between fatty liver and metabolic alterations and to stress the need of assessing fatty liver independently from alcohol consumption and other coexisting causes of liver disease. The peculiarity of NAFLD/MAFLD lies in the presence of a higher risk of not only – as expected – liver-related events but also of extrah…
The Role of Transient Elastography in NAFLD
On the ground of its rising prevalence, nonalcoholic fatty liver disease (NAFLD) is nowadays the most relevant liver disease worldwide, affecting about 25% of the general population [1].
NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease
Background and Aims: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis. Methods: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n = 124). Results: The NR1H4 rs35724 CC genotype, after adjusting for clinic-metabolic and genetic conf…
Antidiabetic Drugs in NAFLD: The Accomplishment of Two Goals at Once?
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in Western countries, accounting for 20–30% of general population and reaching a prevalence of 55% in patients with type 2 diabetes mellitus (T2DM). Insulin resistance plays a key role in pathogenic mechanisms of NAFLD. Many drugs have been tested but no medications have yet been approved. Antidiabetic drugs could have a role in the progression reduction of the disease. The aim of this review is to summarize evidence on efficacy and safety of antidiabetic drugs in patients with NAFLD. Metformin, a biguanide, is the most frequently used drug in the treatment of T2DM. To date 15 randomized controlled t…
The burden of hepatocellular carcinoma in non-alcoholic fatty liver disease: Screening issue and future perspectives
In recent decades, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the Western world, and the occurrence of its complications, such as hepatocellular carcinoma (HCC), has rapidly increased. Obesity and diabetes are considered not only the main triggers for the development of the disease, but also two independent risk factors for HCC. Single nucleotide polymorphisms (such as PNPLA3, TM6SF2 and MBOAT7) are related to the susceptibility to the development of HCC and its progression. Therefore, an appropriate follow-up of these patients is needed for the early diagnosis and treatment of HCC. To date, international guidelines recommend the use of ultrasonogr…
Association Between PNPLA3 rs738409 C>G Variant and Liver-Related Outcomes in Patients with Non-alcoholic Fatty Liver Disease
Background & Aims Patients with nonalcoholic fatty liver disease (NAFLD) have an increased risk for liver-related complications, such as decompensation, hepatocellular carcinoma (HCC), and death; the severity of liver fibrosis and metabolic comorbidities are the main risk factors. A single nucleotide polymorphism in patatin-like phospholipase domain-containing-3 (PNPLA3) gene is associated with higher prevalence of liver damage and HCC, but there are no data from prospective studies of outcomes of patients with this polymorphism. We investigated whether the common rs738409 variant in PNPLA3 gene associates with the occurrence of liver-related events and death in a large cohort of patients w…
Interplay between non-alcoholic fatty liver disease and cardiovascular risk in an asymptomatic general population
BACKGROUND AND AIMS Non-alcoholic fatty liver (NAFLD) is a major cause of liver disease worldwide leading also to a higher risk of cardiovascular events. We aimed to evaluate the impact of fatty liver and fibrosis on cardiovascular risk in a general population. METHODS Five hundred and forty-two subjects included in the community-based ABCD (Alimentazione, Benessere Cardiovascolare e Diabete) study were recruited. Steatosis (controlled attenuation parameter > 288 dB/m) and severe fibrosis (low risk, liver stiffness measurement [LSM] < 7.9 KPa with M probe and < 5.7 KPa with XL probe; intermediate risk, LSM 7.9-9.5 KPa with M probe and 5.7-9.2 KPa with XL probe; high risk, LSM ≥ 9.6 KPa with…
Monitoring Occurrence of Liver-Related Events and Survival by Transient Elastography in Patients With Nonalcoholic Fatty Liver Disease and Compensated Advanced Chronic Liver Disease
[Background & Aims] Patients with advanced fibrosis related to nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatic and extrahepatic complications. We investigated whether, in a large cohort of patients with NAFLD and compensated advanced chronic liver disease, baseline liver stiffness measurements (LSMs) and their changes can be used to identify patients at risk for liver-related and extrahepatic events.
Effect of pharmacological interventions and placebo on liver Histology in nonalcoholic steatohepatitis: A network meta-analysis
Background: The aims of this study were to quantify the histological improvement and its risk factors in patients with NASH enrolled in the placebo arms of randomized controlled trials (RCTs), and to indirectly compare the effect of several investigational drugs for NASH on validated histological outcomes.Data synthesis: A comprehensive search was conducted to detect phase 2 and 3 RCTs comparing pharmacological interventions in patients with NASH. According to Food and Drug Administra-tion (FDA) recommendations, primary outcomes included: 1) NASH resolution without wors-ening of fibrosis; 2) At least 1-point reduction in fibrosis without worsening of NASH. Meta -analysis and meta-regression…
PNPLA3 rs738409 C>G Variant Predicts Fibrosis Progression by Noninvasive Tools in Nonalcoholic Fatty Liver Disease
Liver fibrosis is the main predictor of events in patients with nonalcoholic fatty liver disease (NAFLD),1 and its evolution is characterized by a nonlinear trend2,3 mostly affected by metabolic risk factors, severity of liver inflammation and steatosis, and weight loss.3 The rs738409 C>G common variant in PNPLA3 gene has been associated with severity of fibrosis and risk of liver-related events in NAFLD.4,5 Noninvasive tests as Fibrosis-4 (FIB-4) and liver stiffness measurement (LSM) are useful to rule-out advanced fibrosis and they could be reliable to predict fibrosis progression.2,6 We aimed to evaluate in patients with NAFLD whether PNPLA3 rs738409 C>G variant impacts on fibrosis…
GEMS, a GEnetic and Metabolic Staging predicting the outcome of non-alcoholic fatty liver disease
Background and Aim: Non-alcoholic fatty liver disease(NAFLD) is an emergent cause of liver-related events(LRE). We have assessed the ability of a composite score based on clinical features, metabolic comorbidities and genetic background, to predict LRE. Methods: 546 consecutive patients with NAFLD were recruited and stratified according to FIB-4(low risk <1.3;intermedium-high risk ≥1.3). LRE were defined as occurrence of HCC or hepatic decompensation. Cox regression multivariate analysis was used to identify baseline variables associated with LRE. Results: Over a median follow-up of 73.8 months, 58 patients experienced LRE(only 1 in the cohort of patients with FIB-4 65 years(HR 17.96), plat…
Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease.
[Background & Aims] Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain.
Presence of Serum Antinuclear Antibodies Does Not Impact Long-Term Outcomes in Nonalcoholic Fatty Liver Disease
Introduction We investigated the longitudinal impact of antinuclear antibody (ANA) on clinical outcomes and survival in nonalcoholic fatty liver disease (NAFLD). Methods ANA were found in 16.9% of 923 biopsy-proven NAFLD patients, but none of them had histologic autoimmune hepatitis (AIH) or developed AIH after a mean follow-up of 106±50 months. Results Although ANA-positive cases had a higher prevalence of nonalcoholic steatohepatitis at baseline, the occurrence of liver-related events, hepatocellula carcinoma, cardiovascular events, extrahepatic malignancy, and overall survival were similar to ANA-negative. Discussion Once AIH has been ruled out, the long-term outcomes and survival are un…