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 & AimsPatients 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.MethodsWe performed a retrospective analysis of consecutive patients with NAFLD (n = 1039) with a histologic diagnosis of F3–F4 fibrosis and/or LSMs>10 kPa, followed for at least 6 months, from medical centers in 6 countries. LSMs were made by FibroScan using the M or XL probe and recorded at baseline and within 1 year from the last follow-up examination. Differences between follow up and baseline LSMs were categorized as: improvement (reduction of more than 20%), stable (reduction of 20% to an increase of 20%), impairment (an increase of 20% or more). We recorded hepatic events (such as liver decompensation, ascites, encephalopathy, variceal bleeding, jaundice, or hepatocellular carcinoma [HCC]) and overall and liver-related mortality during a median follow-up time of 35 months (interquartile range, 19–63 months).ResultsBased on Cox regression analysis, baseline LSM was independently associated with occurrence of hepatic decompensation (hazard ratio [HR], 1.03; 95% CI, 1.02–1.04; P < .001), HCC (HR, 1.03; 95% CI, 1.00–1.04; P = .003), and liver-related death (HR, 1.02; 95% CI, 1.02–1.03; P = .005). In 533 patients with available LSMs during the follow-up period, change in LSM was independently associated with hepatic decompensation (HR, 1.56; 95% CI, 1.05–2.51; P = .04), HCC (HR, 1.72; 95% CI, 1.01–3.02; P = .04), overall mortality (HR, 1.73; 95% CI, 1.11–2.69; P = .01), and liver-related mortality (HR, 1.96; 95% CI, 1.10–3.38; P = .02).ConclusionsIn patients with NAFLD and compensated advanced chronic liver disease, baseline LSM and change in LSM are associated with risk of liver-related events and mortality.     

Lower levels of plasma NT-proBNP are associated with higher prevalence of NASH in patients with biopsy-proven NAFLD

Background and aimsEmerging evidence suggests that plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are decreased in patients with imaging-defined nonalcoholic fatty liver disease (NAFLD), but no data are currently available on the association between plasma NT-proBNP levels and the histological severity of NAFLD.Methods and resultsWe enrolled 351 (73.5% men) consecutive adult patients with biopsy-proven NAFLD without a prior history of cardiovascular disease (CVD). Plasma NT-proBNP levels were measured using a commercially available immunochemical system (VITROS® 5600, Johnson, New Jersey). Fifty-three percent of these subjects had nonalcoholic steatohepatitis (NASH). After stratification of patients by plasma NT-proBNP tertiles; compared to those in the 1st tertile (NT-proBNP ≤16 pg/ml), the odds ratio for NASH was 0.52 (95% CI 0.29–0.95) in patients in the 2nd tertile (NT-proBNP of 17–33 pg/ml) and 0.49 (95% CI 0.26–0.93) in those in the 3rd tertile (NT-proBNP ≥34 pg/ml) of plasma NT-proBNP levels, even after adjustment for age, sex, body mass index, homeostasis model assessment (HOMA)-estimated insulin resistance, pre-existing diabetes, hypertension, and dyslipidemia.ConclusionIn subjects with biopsy-proven NAFLD without known CVD, this cross-sectional study shows for the first time, that lower plasma NT-proBNP levels are strongly associated with a higher prevalence of NASH.     

Role of diabetologists in the management of nonalcoholic fatty liver disease: Primary prevention and screening/management of fibrosis and cirrhosis

Background and aimsNonalcoholic fatty liver disease (NAFLD) is a common condition, especially among individuals with type 2 diabetes (T2D). Presence of T2D increases the risk of progression of simple steatosis to more severe liver conditions, such as nonalcoholic steatohepatitis (NASH) and fibrosis (NASH-fibrosis). Since majority of patients with T2D are managed by diabetologists (including physicians and endocrinologists), their roles in the management of coexisting NAFLD are not well defined, partly due to lack of unambiguous guidelines.MethodsA literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till January 2022, using relevant keywords (nonalcoholic fatty liver disease and diabetologist; screening of NASH; management of NASH) to extract relevant studies describing prevention and screening of NAFLD/NASH, especially in people with T2D.ResultsDiabetologists have two main roles for the management of patients with T2D and coexisting NAFLD. The most important role is to prevent the development of NASH-fibrosis in patients with simple steatosis (primary prevention). This can be achieved by reinforcing the importance of lifestyle measures, and by early use of glucose-lowering agents with beneficial effects on the liver. The second important role of diabetologists is to screen all patients with T2D for liver fibrosis and compensated cirrhosis, and provide appropriate referral for timely management of complications (secondary prevention).ConclusionDiabetologists can play a central role in mitigating the epidemic of NAFLD in individuals with T2D. However, diabetologists need to be aware about their roles in NASH-fibrosis prevention and screening. Furthermore, longitudinal studies should explore the role of newer glucose-lowering drugs in the primary prevention of NASH-fibrosis in individuals with coexisting T2D and simple steatosis.     

Real-world treatment and health care resource use among severe asthma patients in Japan

BackgroundThere are limited studies on healthcare resource use (HCRU) among adult asthma patients in Japan using real-world evidence, and analysis on acute treatment and associated costs stratified by disease severity is further limited. This study aimed to characterize the disease burden of severe asthma patients in Japan in terms of HCRU and comorbid medical conditions, with particular interest in oral corticosteroid (OCS) dependency.MethodsThis retrospective cohort study of asthma patients used data from a claims database of diagnosis procedure combination hospitals in Japan. The severe asthma cohort included patients treated with OCS for more than 180 days in one year before the index date, with at least one asthma diagnosis claim. Comorbidity and drug use in the look-back period, HCRU, assumed OCS-related adverse events, and asthma exacerbations in the follow-up period were analyzed.ResultsCosts associated with the treatment of severe asthma were approximately twice that of mild/moderate asthma, and the annual median cost of patients hospitalized due to asthma reached ¥448,000 (USD $4073). Annual asthma exacerbation rate was higher in the severe asthma cohort than in the mild/moderate cohort. Patients with longer OCS use in the previous year had higher risks of secondary adrenal insufficiency, osteoporosis, and pneumonia in the following year.ConclusionsOCS use among asthma patients in Japan incurred greater medical and economic burden. Better understanding of the disease characteristics including the severity of asthma and appropriate management of disease burden will lead to more optimal use of healthcare resources in Japan.     

Evaluation of thrombocytopenia in patients with non-alcoholic fatty liver disease without cirrhosis

Introduction and objectivesNon-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. It is often related to metabolic syndrome, presenting an increased risk of advanced liver disease and cardiovascular-related death. In some etiologies of chronic liver disease, thrombocytopenia has been associated not only with advanced stages of fibrosis but also with autoimmune disease. In NAFLD, however, its prevalence and related factors are still unknown. The aim of this study is to evaluate the prevalence of thrombocytopenia in NAFLD patients without cirrhosis and to investigate its related risk factors.Patients and methodsThis was a retrospective study carried out in two tertiary hospitals in the South and Southeast regions of Brazil. Patients diagnosed with NAFLD by liver biopsy were included. Those with other causes of liver disease and/or cirrhosis were excluded. For analysis, patients were divided into two groups, with and without thrombocytopenia. Data was analyzed using a significance level of 5%.Results441 non-cirrhotic patients with NAFLD (evaluated by liver biopsy) were included in the study. The prevalence of thrombocytopenia was 3.2% (14/441 patients). In the comparative analysis between groups, thrombocytopenia was associated with male sex (p = 0.007) and level of hemoglobin (p = 0.023).ConclusionThrombocytopenia is an infrequent event in NAFLD patients without cirrhosis and is related with male sex and higher hemoglobin levels.     

Association between positivity of serum autoantibodies and liver disease severity in patients with biopsy-proven NAFLD

Background and aimsSome previous studies reported serum autoantibody positivity in patients with nonalcoholic fatty liver disease (NAFLD). The clinical significance of these findings remains uncertain. We aimed to investigate the association between the presence of serum autoantibodies and liver disease severity in NAFLD.Methods and resultsA total of 388 consecutive patients with biopsy-proven NAFLD were included in the study. Various serum autoantibodies (including also anti-nuclear antibodies [ANA]) were detected by indirect immunofluorescent or immunoblotting assays. Overall, 84 (21.6%) patients with biopsy-confirmed NAFLD had positivity for at least one of the measured serum autoantibodies. ANA positivity was present in 50 (12.9%) patients, whereas anti-U1RNP or pANCA antibodies were detectable in 9 (2.3%) and 6 (1.5%) patients, respectively. Multivariate logistic regression analysis showed that ANA positivity (adjusted-odds ratio: 4.51, 95%CI: 1.77–11.5; P = 0.002) or positivity of any serum autoantibodies (adjusted-odds ratio: 3.14, 95%CI: 1.30–7.62; P = 0.01) were independently associated with advanced liver fibrosis (stages F3–F4). In serum autoantibody/ANA-positive patients, the proportion of those with advanced fibrosis was also greater among carriers of PNPLA3 rs738409 GG or CG than among those carrying PNPLA3 rs738409 CC genotype.ConclusionsSerum autoantibody positivity was independently associated with advanced liver fibrosis in patients with biopsy-proven NAFLD. The presence of serum autoantibodies in patients with advanced fibrosis occurred more frequently amongst those carrying PNPLA3 rs738409 GG or CG genotypes.     

Low levels of osteocalcin,but not CTX or P1NP,are associated with nonalcoholic hepatic steatosis and steatohepatitis

AimThe association of bone turnover with the incidence and progression of nonalcoholic fatty liver disease (NAFLD) is unclear. We aimed to evaluate serum levels of bone turnover markers in relation to NAFLD and nonalcoholic hepatic steatohepatitis (NASH).MethodsTwo cohorts were involved in our study. For the first cohort, 370 participants without NAFLD were retrospectively recruited and followed up for incident NAFLD according to ultrasound. For the second cohort, 562 subjects who underwent liver biopsy were included and grouped into non-NAFLD, non-NASH or NASH according to the NASH Clinical Research Network system. The bone turnover markers osteocalcin, C-terminal telopeptide (CTX) and N-terminal propeptide of type-1 procollagen (P1NP) were measured.ResultsBaseline osteocalcin was significantly lower in subjects who developed NAFLD (13.93 [11.03;16.39] versus 18.24 [15.45;22.47] ng/ml, P < 0.001), with a median of 26.4 months of follow-up. Low levels of osteocalcin, but not CTX or P1NP, was an independent predictor of incident NAFLD (OR 0.755 [95%CI 0.668; 0.855] P < 0.001). Moreover, the osteocalcin level was negatively associated with the degree of liver steatosis. Furthermore, subjects with NASH had significantly lower osteocalcin than non-NASH and non-NAFLD group (13.28 [10.49;16.59] versus 14.91 [12.45;18.09] versus 18.21 [15.04;22.05] ng/ml, all P < 0.001). A low osteocalcin level was an independent risk factor for NASH (OR for highest versus lowest quartile: 0.282 [0.147;0.543] P < 0.001).ConclusionLow level of osteocalcin, but not CTX or P1NP, was associated with NAFLD and NASH, indicating its potential role as an important endocrine regulator of hepatic energy metabolism.     

Prevalence of liver fibrosis in an unselected general population with high prevalence of obesity and diabetes mellitus. Time for screening?

IntroductionCirrhosis and liver cancer are currently common causes of death worldwide. The global epidemic of obesity has increased the incidence of nonalcoholic fatty liver disease (NAFLD) and cirrhosis in recent years. Advanced fibrosis increases the morbimortality rate in NAFLD. The Mexican population has one of the highest prevalence of obesity and diabetes mellitus (DM) worldwide.AimTo determine the prevalence of advanced liver fibrosis in Mexican general population.MethodsAdult individuals, without a history of liver disease nor heavy alcohol consumption were randomly sampled from 20,919 participants of a health and nutrition survey applied to the general population. Clinical and laboratory evaluations were performed to calculate the NAFLD fibrosis score (NFS) (an extensively validated non-invasive method). Two cut-off points were used. Advanced fibrosis was defined as a result >0.676.ResultsIn total 695 individuals were included. The mean age was 47.8 ± 16.4. The majority were between 20 and 50 years (59%), 70.2% were female, 35.5% showed obesity and 15.8% DM. The 93% had normal serum ALT. Based on the NFS results, 56 individuals (8.1%) had a high probability of fibrosis. Most patients from this subgroup showed normal serum ALT (92.9%), 89.3% were >45 yr. old, 52% were obese and 27% suffered from DM.ConclusionsBased on these results, 8.1% of Mexican general population without a history of liver disease is at high risk of having advanced liver fibrosis and complications and death derived from cardiovascular disease and cirrhosis. Most of them showed normal ALT serum levels.     

Disease severity predicts higher healthcare costs among hospitalized nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) patients in Spain

The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) presents many public health challenges, including a substantial impact on healthcare resource utilization and costs. There are important regional differences in the burden of NAFLD/NASH, and Spain-specific data are lacking. This retrospective, observational study examined the impact of liver disease severity, comorbidities, and demographics on healthcare resource utilization and costs in Spain.NAFLD/NASH patients in the Spanish National Health System''s Hospital Discharge Records Database (1/1/2006 to 4/30/2017) were categorized into disease severity cohorts as NAFLD/NASH overall, NAFLD/NASH non-progressors, compensated cirrhosis (CC), decompensated cirrhosis (DCC), liver transplant (LT), or hepatocellular carcinoma (HCC). Patients were followed from index date until the earliest of 6 months, disease progression, end of coverage, death, or end of study. Within each cohort, pre- and post-index healthcare resource utilization and costs per patient per month (PPPM) were calculated.A total of 8,205 patients (mean age 58.4; 54% male) were identified; 5,984 (72.9%) were non-progressors, 139 (1.7%) progressed to CC, 2,028 (24.7%) to DCC, 115 (1.4%) to LT, and 61 (0.7%) to HCC. Pre-index comorbidity burden was high across disease cohorts, and the frequency of comorbidities increased with disease severity. From pre- to post-index, average length of stay (LOS) increased significantly (23%–41%) as did all-cause PPPM costs (44%–46%), with significantly longer LOS and costs in patients with increasing disease severity.Progression of NAFLD/NASH was associated with significantly higher costs and longer LOS. A coordinated approach is needed to manage resources and costs in Spain.     

Visceral adipose tissue quality was associated with nonalcoholic fatty liver disease,independent of its quantity

Background and aimsNonalcoholic fatty liver disease (NAFLD) is a serious liver disease. Recent studies have shown that both visceral adipose tissue (VAT) quantity and density (as an indirect measure of quality) are associated with metabolic profiles. Therefore, we investigated the association between VAT quantity and quality, and the prevalence and incidence of NAFLD.Methods and resultsIn this cross-sectional, retrospective cohort study, the prevalence and incidence of NAFLD were analyzed in 627 and 360 middle-aged subjects, respectively. VAT was evaluated using an unenhanced computed tomography scan, while NAFLD was evaluated using ultrasonography. The VAT area was normalized to the square value of the subjects’ height in meters, the visceral fat area (VFA) index. The VAT density was described as the visceral fat density (VFD). The VFA index and VFD had an interaction effect on the prevalence of NAFLD (P = 0.0059). The VFA index (adjusted odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01–1.07; P = 0.0145, per 1.0 cm²/m²) and the VFD (OR, 0.90; 95% CI, 0.84–0.96; P = 0.0026, per 1.0 Hounsfield unit [HU]) were independently associated with the prevalence of NAFLD. In our cohort, 36 subjects developed NAFLD. The VFD (adjusted hazards ratio [HR], 0.84; 95% CI, 0.77–0.91; P < 0.0001, per 1.0 HU) was independently associated with the incidence of NAFLD, whereas the VFA index was not.ConclusionBoth the VFA index and VFD were independently associated with NAFLD prevalence. The VFD might be more related to the incidence of NAFLD than the VFA index.     

Effect of pharmacological interventions and placebo on liver Histology in nonalcoholic steatohepatitis: A network meta-analysis

BackgroundThe 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 synthesisA comprehensive search was conducted to detect phase 2 and 3 RCTs comparing pharmacological interventions in patients with NASH. According to Food and Drug Administration (FDA) recommendations, primary outcomes included: 1) NASH resolution without worsening of fibrosis; 2) At least 1-point reduction in fibrosis without worsening of NASH. Meta-analysis and meta-regressions were conducted on placebo arms, while network meta-analysis was performed on intervention arms.A total of 15 RCTs met the eligibility criteria. The meta-analysis on placebo arms showed a pooled estimate rate of 17% (95%C.I. 12%–23%;I² = 86%; p < 0.01) for NASH resolution without worsening of fibrosis and of 21% (95%C.I. 13%–31%;I² = 84%; p < 0.01) for ≥1stage improvement of fibrosis without worsening of NASH. Phase 3 (vs Phase 2)RCTs, older age and higher AST levels were significantly associated with progression of liver disease by univariate meta-regression. At network meta-analysis, Semaglutide (P-score 0.906), Pioglitazione alone (score 0.890) and plus Vitamin E (0.826) had the highest probability of being ranked the most effective intervention for NASH resolution without worsening of fibrosis, while Aldafermin (0.776), Lanifibranor (0.773) and Obeticholic acid (0.771) had the highest probability to achieve ≥1 stage of fibrosis improvement without worsening of NASH.ConclusionThis study confirms the heterogeneity of histological progression of untreated patients with NASH and provides evidence to stratify patients according to identified risk factors in future RCTs of combination therapies. PROSPERO CRD42021287205.     

In the Era of Direct-Acting Antivirals,Liver Transplant Delisting Due to Clinical Improvement for Hepatitis C Remains Infrequent

Background / AimsStudies have suggested marked increases in transplant delisting due to clinical improvement for patients with hepatitis C virus (HCV) associated cirrhosis in the era of direct acting antivirals (DAAs). This study provides a ‘real world’ assessment of waitlist dynamics for HCV transplant candidates in the current era.MethodsThis was a retrospective cohort study of adults waitlisted for liver transplant (LT) alone between 1/1/2005-12/31/2018 using national US data. The post-DAA era included all listings occurring after 1/1/2013. Temporal trends in waitlisting, patient characteristics and outcomes with decompensated cirrhosis were evaluated. Adjusted competing risks models assessed the interaction of DAA-era and HCV history on (i) waitlist mortality, and (ii) delisting due to clinical improvement.ResultsOverall listing rates for HCV patients have decreased in the DAA era and particularly with Model for End-stage Liver Disease score ≥15 and ≥30. Rates of refractory ascites and severe encephalopathy at listing have increased. Delisting due to clinical improvement remains low (6.1% for 2013-2017 versus 5.2% for 2009-2012 versus 4% for 2005-2008; p < .001) and, for many, ascites (46.5%) and encephalopathy (30.5%) persist at delisting. Waitlist recovery is more frequent for HCV patients post-DAA (adjusted SHR 1.78 vs pre-DAA, 95% CI: 1.58-2.02; p < .001), while improvements in waitlist mortality by era are similar to non-HCV candidates (adjusted SHR 0.74 [95% CI: 0.7-0.78; p < .001] and 0.77 [95% CI: 0.74-0.8; p < .001], respectively).ConclusionListing rates for decompensated HCV cirrhosis have decreased in the DAA era. Delisting of HCV patients for clinical improvement has increased, but remains infrequent and many continue to experience considerable morbidity.     

Insulin resistance,but not insulin response,during oral glucose tolerance test (OGTT) is associated to worse histological outcome in obese NAFLD

Background and aimObese subjects are at high risk of nonalcoholic fatty liver disease (NAFLD) and diabetes (T2D) due to insulin resistance (IR). Since high glucose levels are as toxic as lipids for hepatic metabolism, we hypothesize that altered response to oral glucose tolerance test (OGTT) is associated to more severe NAFLD with significant/advanced liver damage.Methods and resultsWe studied 90 subjects with morbid obesity (73F/17M, BMI = 43.2 ± 5,9 kg/m²) undergoing bariatric surgery and intraoperative liver biopsy, and measured HbA1c, HOMA-IR (fasting Glucose x Insulin/22.5), OGTT glucose and insulin profile, and calculated OGIS (muscle insulin sensitivity), hepatic-IR (glucose [AUC_0-30] x insulin [AUC_0-30]) during OGTT, insulin response as (insulin [dAUC_0-120]/glucose [dAUC_0-120] or Insulinogenic Index (IGI = (I₃₀–I₀)/(G₃₀-G₀)). Patients were divided in 3 groups according to liver biopsy: A (no-NAFLD, 23%), B (simple steatosis (SS), 53%) and C (NASH, 24%) with similar age, gender and BMI. Diabetes was 0% in no-NAFLD, 13% in SS, 35% in NASH. During OGTT, OGIS decreased from A to C (422 vs 360 vs 338, p < 0.01). Increased insulin concentrations, HbA1c, HOMA-IR and OGIS, not Hep-IR, were strongly associated to hepatic steatosis (p = 0.03, p = 0.0001 and p = 0.01 respectively). Hepatic fibrosis stage was mild as most of the patients had fibrosis grade-1 (69% vs. 8% no fibrosis) and associated to fasting insulin, HbA1c and HOMA-IR. dAUC-I/dAUC-G was similar in the 3 groups, while only AUC-I was strongly associated to steatosis (r = 0.35, p = 0.005), but not to fibrosis.ConclusionsIn morbid obesity indexes of IR, and not of insulin response, are markers of histological severity of liver disease.     

Spontaneous portosystemic shunt embolization in liver transplant recipients with recurrent hepatic encephalopathy

Introduction and objectivesSpontaneous portosystemic shunts (SPSS) are a common cause of recurrent hepatic encephalopathy (HE). Shunt occlusion is an effective and safe procedure when performed in patients with cirrhosis and preserved liver function. We aimed to describe our experience with SPSS embolization after liver transplantation (LT).PatientsWe identified five patients who underwent SPSS embolization after LT. Clinical, biochemical and technical procedure data were collected.ResultsAt presentation, all patients had developed graft cirrhosis and HE after LT. Median Model for End-stage Liver Disease (MELD) at embolization was 9 (range 7-12), median Child-Pugh was 8 (range 7-9). Splenorenal and mesocaval shunt were the most frequent types of SPSS found. Three patients have been completely free of HE. Of the two patients who had HE recurrence after embolization, one patient had two episodes of HE which was controlled well with medications. The other patient required three embolizations because of recurrent HE. Median follow-up was 4.4 years (range 1.0-5.0) and MELD score at last follow up was 13 (range 10-18) and median Child-Pugh score B, 7 points (range 5-12).ConclusionsSPSS can be considered as a cause of HE after LT. SPSS embolization is feasible and safe in LT recipients.     

Nonalcoholic fatty liver disease and risk of incident young-onset hypertension: Effect modification by sex

Background and aimsAlthough nonalcoholic fatty liver disease (NAFLD) and hypertension are increasingly common among young adults, it is uncertain if NAFLD affects incidence of young-onset hypertension, and if the association is modified by sex. We investigated potential effect modification by sex on the association between NAFLD and incident hypertension in young adults (<40 years).Method and resultsThis cohort study comprised 85,789 women and 67,553 men aged <40 years without hypertension at baseline. Hepatic steatosis was assessed by liver ultrasound and classified as mild or moderate/severe. Hypertension was defined as blood pressure (BP) ≥130/80 mmHg; self-reported history of physician-diagnosed hypertension; or current use of BP-lowering medications. Cox proportional hazard models were used to estimate hazard ratios (HRs; 95% confidence intervals [CIs]) for incident hypertension by NAFLD status (median follow-up 4.5 years). A total of 25,891 participants developed incident hypertension (incidence rates per 10³ person-years: 15.6 for women and 63.5 for men). Multivariable-adjusted HRs (95% CIs) for incident hypertension comparing no NAFLD (reference) with mild or moderate/severe NAFLD were 1.68 (1.56–1.80) and 1.83 (1.60–2.09) for women and 1.21 (1.17–1.25) and 1.23 (1.17–1.30) for men, respectively. Stronger associations were consistently observed between NAFLD and incident hypertension in women, regardless of obesity/central obesity (all p-values for interaction by sex <0.001).ConclusionsNAFLD is a potential risk factor for young-onset hypertension with a relatively greater impact in women and in those with more severe hepatic steatosis.     

Type 2 diabetes mellitus in metabolic-associated fatty liver disease vs. type 2 diabetes mellitus non-alcoholic fatty liver disease: a longitudinal cohort analysis

Introduction and ObjectivesType 2 Diabetes Mellitus (T2DM) is comorbidity commonly presenting with fatty liver. A recently proposed definition of "metabolic associated fatty liver disease" (MAFLD) is thought to replace non-alcoholic fatty liver disease (NAFLD). Yet, despite the significant prevalence of T2DM among fatty liver, there remains limited evidence on the impact of the change in the definition of T2DM.Materials and MethodsThe current study uses data from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Survival analysis was conducted with a cox regression and sub-distribution hazard ratio for competing risk events.Results6727 patients had a diagnosis of T2DM. 4982 individuals with T2DM had MAFLD and 2032 were MAFLD(+)/NAFLD(-), while 2950 patients were MAFLD(+)/NAFLD(+). The new definition increased fatty liver diagnosis by 68.89%. Patients who were classified as MAFLD(+)/NAFLD(-) were at a higher risk of major adverse cardiovascular events, advanced fibrosis, all-cause and cardiovascular-related mortality compared to MAFLD(+)/NAFLD(+). In MAFLD(+)/NAFLD(-), viral hepatitis significantly increases the odds of advanced fibrosis (OR: 6.77, CI: 3.92 to 11.7, p < 0.001) and all-cause mortality (HR: 1.75, CI: 1.29 to 2.40, p < 0.001).ConclusionsThe identification and treatment of NAFLD in patients with T2DM is a major concern and the premature change to MAFLD results in an over-diagnosis of fatty liver, exaggerated mortality, and morbidity in patients with T2DM. The definition of MAFLD causes further heterogeneity in fatty liver disease/NAFLD.     

PNPLA3 polymorphism influences the association between high-normal TSH level and NASH in euthyroid adults with biopsy-proven NAFLD

AimWe aimed to evaluate the association between serum thyroid stimulating hormone (TSH) levels, within the reference range, and the histological severity of nonalcoholic fatty liver disease (NAFLD), and whether this association was modulated by the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism.Materials and methodsWe enrolled 327 euthyroid individuals with biopsy-proven NAFLD, who were subdivided into two groups, i.e., a ‘strict-normal’ TSH group (TSH level 0.4 to 2.5 mIU/L; n = 283) and a ‘high-normal’ TSH group (TSH level 2.5 to 5.3 mIU/L with normal thyroid hormones; n = 44). Logistic regression analyses were performed to assess the association between TSH status and presence of nonalcoholic steatohepatitis (NASH) after stratifying subjects by PNPLA3 genotypes.ResultsCompared to strict-normal TSH group, patients with high-normal TSH levels were younger and had a greater prevalence of NASH and higher histologic NAFLD activity score. After stratifying by PNPLA3 genotypes, the significant association between high-normal TSH levels and presence of NASH was restricted only to carriers of the PNPLA3 G risk allele and remained significant even after adjustment for potential confounding factors (adjusted-odds ratio: 3.279; 95% CI: 1.298–8.284; P = 0.012).ConclusionIn euthyroid individuals with biopsy-proven NAFLD, we found a significant association between high-normal TSH levels and NASH. After stratifying by PNPLA3 rs738409 genotypes, this association was observed only among carriers of the PNPLA3 G risk allele.     

Upregulated NLRP3 inflammasome activation is attenuated by anthocyanins in patients with nonalcoholic fatty liver disease: A case-control and an intervention study

ObjectivesDespite the recent attention focused on the roles of the NLRP3 inflammasome in the pathogenesis of metabolic and inflammatory diseases, little is known about the activation status of NLRP3 inflammasome in patients with nonalcoholic fatty liver disease (NAFLD). The present study aimed to investigate whether inflammasomes activation is upregulated in patients with NAFLD and the upregulation can be attenuated by anthocyanins, which are polyphenols with known anti-inflammatory activities.MethodsThis study included a case-control study and a randomized controlled intervention trial. In the first part, NAFLD patients and healthy controls were recruited from a cohort of railroad workers. In the second part, NAFLD patients were randomly assigned to receive either capsules of anthocyanins (320 mg daily) or placebo for 12 weeks. A series of genes and factors associated with activation of NLRP3 inflammasome in subjects’ plasma and peripheral blood mononuclear cells (PBMCs) were analyzed.ResultsCompared with healthy controls, the mRNA levels of NLRP3 inflammasome components (NLRP3, caspase-1, interleukin (IL)-1β, and IL-18) were significantly upregulated in the PBMCs of NAFLD patients. Consistently, plasma levels of mature IL-1β and IL-18 in NAFLD patients were significantly higher than in controls. After anthocyanin administration, both mRNA expression of NLRP3 inflammasome components (caspase-1, IL-1β, and IL-18) in PBMCs and plasma levels of IL-1β and IL-18 decreased dramatically in NAFLD patients compared with controls.ConclusionsThis study has demonstrated that the activation of NLRP3 inflammasome is highly increased in NAFLD patients, but it can be markedly suppressed by anthocyanins, which provides a rationale for the development of anti-inflammatory therapies in NAFLD.     

Association between non-alcoholic fatty liver disease and impaired cardiac sympathetic/parasympathetic balance in subjects with and without type 2 diabetes—The Cooperative Health Research in South Tyrol (CHRIS)-NAFLD sub-study

Background and aimsCardiovascular disease (CVD) is the leading cause of death in patients with non-alcoholic fatty liver disease (NAFLD), both with and without type 2 diabetes mellitus (T2DM). Cardiac autonomic dysfunction is a risk factor for CVD morbidity and mortality. The aim of this pilot study was to assess whether there is an association between NAFLD and impaired cardiac autonomic function.Methods and resultsAmong the first 4979 participants from the Cooperative Health Research in South Tyrol (CHRIS) study, we randomly recruited 173 individuals with T2DM and 183 age- and sex-matched nondiabetic controls. Participants underwent ultrasonography and vibration-controlled transient elastography (Fibroscan®, Echosens) to assess hepatic steatosis and liver stiffness. The low-to-high-frequency (LF/HF) power ratio and other heart rate variability (HRV) measures were calculated from a 20-min resting electrocardiogram (ECG) to derive a measure of cardiac sympathetic/parasympathetic imbalance. Among the 356 individuals recruited for the study, 117 had NAFLD and T2DM, 56 had T2DM alone, 68 had NAFLD alone, and 115 subjects had neither condition. Individuals with T2DM and NAFLD (adjusted odds ratio [OR] 4.29, 95% confidence intervals [CI] 1.90–10.6) and individuals with NAFLD alone (adjusted OR 3.41, 95% CI 1.59–7.29), but not those with T2DM alone, had a substantially increased risk of having cardiac sympathetic/parasympathetic imbalance, compared with those without NAFLD and T2DM. Logistic regression models were adjusted for age, sex, body mass index (BMI), hypertension, dyslipidemia, insulin resistance, hemoglobin A1c (HbA1c), C-reactive protein (CRP), and Fibroscan®-measured liver stiffness.ConclusionsNAFLD was associated with cardiac sympathetic/parasympathetic imbalance, regardless of the presence or absence of T2DM, liver stiffness, and other potential confounding factors.     

The prevalence of nonalcoholic fatty liver disease in Chinese adults screened by vibration controlled transient elastography and its diagnostic discrepancy compared with ultrasound

BackgroundThe prevalence of non-alcoholic fatty liver disease (NAFLD) in China as assessed using vibration-controlled transient elastography (VCTE) and its consistency with ultrasound is still unknown. We aimed to conduct a head-to-head comparison of consecutive measurements of NAFLD with ultrasound or VCTE to evaluate the discrepancy in the prevalence and distribution of NAFLD screened by two non-invasive techniques.MethodsWe collected VCTE and ultrasound examination data from 4,388 participants who underwent health check-ups at the Health Promotion Center of Jiangsu Province Hospital between January 2017 and December 2019. The major outcome was the presence of hepatic steatosis, which was defined as a median controlled attenuation parameter (CAP) ≥ 248 dB/m by VCTE or the definition of steatosis by ultrasound.ResultsAmong the 4,388 participants, 2,214 were diagnosed with NAFLD by VCTE (CAP ≥ 248 dB/m, 50.46%). Participants with severe steatosis (CAP ≥ 280 dB/m) were commonly male (77.94% vs. 50.38%, P < 0.001), were obese (45.09% vs. 1.79%, P < 0.001), had a worse metabolic profile, had elevated liver enzyme levels, and had advanced fibrosis. The prevalence of ultrasound-diagnosed NAFLD was 56.42%. After consistency analysis, VCTE and ultrasound showed moderate agreement regarding the diagnosis of NAFLD (κ = 0.475). We then compared the characteristics and clinical features of the four groups classified by the diagnosis results of the two techniques. NAFLD participants diagnosed by VCTE only were older, more obese, and had worse metabolic and biochemical profiles than NAFLD participants diagnosed by ultrasound only; in particular, the former had a higher proportion of abnormal alanine aminotransferase and aspartate aminotransferase levels and a higher proportion of advanced fibrosis than the latter.ConclusionsMore than half of Chinese adults were affected by NAFLD according to VCTE. Screening based on VCTE is more likely to identify NAFLD patients with severe clinical features than ultrasound. Therefore, VCTE is a more practical non-invasive tool for the screening and follow-up of NAFLD in China.