Liver Fibrosis In Non-alcoholic Fatty Liver Disease Research Articles

The Annexin A2-Notch regulatory loop in hepatocytes promotes liver fibrosis in NAFLD by increasing osteopontin expression

BackgroundThe mechanisms underlying the progression of liver disease from simple hepatic steatosis to advanced nonalcoholic steatohepatitis (NASH) and liver fibrosis warrant further investigation. Increased mRNA levels of Annexin A2 protein (Anxa2) have been observed in patients with NASH. However, the role of Anxa2 in NASH remains unclear. MethodsThe protein levels of Anxa2 were analyzed in the livers of mice and patients with NASH. Anxa2-knockout and -knockdown mice were generated, and NASH was induced through a high fructose, palmitate, and cholesterol (FPC) diet or methionine- and choline-deficient (MCD) diet. FindingsWe found elevated expression of Anxa2 in the livers of patients and mice with NASH. Anxa2 knockdown but not knockout ameliorated liver fibrosis in both FPC and MCD diet–fed mice. Liver-specific Anxa2 overexpression increased collagen deposition in mice fed a normal diet. Mechanistically, Anxa2 overexpression in hepatocytes promoted hepatic stellate cell activation in a paracrine manner by increasing osteopontin expression. Notch inhibition suppressed the exogenous overexpression of Anxa2-induced osteopontin and endogenous Anxa2 expression. Additionally, Anxa2 overexpression accelerated the progression of nonalcoholic fatty liver disease (NAFLD) in mice fed a high-fat diet. Moreover, Anxa2 levels were higher in NAFLD patients with advanced liver fibrosis than in those with mild liver fibrosis, as determined using the Gene Expression Omnibus database. InterpretationIn conclusion, we found increased Anxa2 expression in hepatocytes promoted liver fibrosis in NASH mice by increasing osteopontin expression. The Anxa2-Notch positive regulatory loop contributes to this process and represents a novel target for the treatment of NASH-related liver fibrosis.

A non-invasive score for nonalcoholic fatty liver disease (NAFLD) cirrhosis

Currently the global prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to be around 25% for the general adult population [1], with estimates over 50% in populations with type 2 diabetes mellitus [2]. Meta-analyses by Dulai et al. (2017) and Taylor et al. (2020) indicate that liver fibrosis in NAFLD is an independent risk factor for all-cause mortality and liver-related mortality [3,4]. This underscores the need to stage NAFLD in order to detect patients with advanced stage fibrosis or cirrhosis

Accuracy of Noninvasive Scoring Systems in Assessing Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Several noninvasive scoring systems have been developed to determine the risk of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD). We examined the diagnostic accuracy of the fibrosis-4 (FIB-4) score and NAFLD fibrosis score (NFS) in patients with biopsy-proven NAFLD. For this meta-analysis, various databases including PubMed (MEDLINE), EMBASE, OVID Medline and the Cochrane Library were systematically searched. After the acquired abstracts were reviewed by two investigators, manuscripts were chosen for a full-text examination. Thirty-six studies evaluating biopsy-proven NAFLD were selected for meta-analysis. A total of 14,992 patients were analyzed. The lower cutoff sensitivity of the FIB-4 score predicting histological fibrosis stage 3 or more (≥F3) was 69%, with specificity of 64%, positive likelihood ratio (LR+) of 1.96, and negative likelihood ratio (LR-) of 0.47. The low baseline sensitivity of the NFS score predicting ≥F3 was 70%, with a specificity of 61%, LR+ of 1.83, and LR- of 0.48. The area under the receiver operating characteristic curve (AUC) values of the FIB-4 score predicting ≥F3 and ≥F2 were 76% and 68%, respectively. The AUC values of the NFS score predicting ≥F3 and ≥F2 were 74% and 60%, respectively. The FIB-4 or NFS test can be used to predict the degree of liver fibrosis in NAFLD, and the diagnostic accuracy resulted as relatively high in fibrosis stages of F3 or higher.

Assessing liver fibrosis in all patients with type 2 diabetes and fatty liver disease: It's time to act now.

Assessing liver fibrosis in all patients with type 2 diabetes and fatty liver disease: It's time to act now.

Study of Non-alcoholic Fatty Liver Disease (NAFLD) by Shear-wave Elastoraphy in Subjects with Metabolic Syndrome

Background: Non-alcoholic fatty liver disease (NAFLD) is well known to have a strong association with metabolic syndrome. The degree of liver fibrosis is related to the clinical course and prognosis. Shear-wave elastography (SWE) provides a precise non-invasive staging of the degree of liver fibrosis in NAFLD. 
 Aims and objectives: To study Non-alcoholic fatty liver disease (NAFLD) by Shear-Wave Elastography (SWE) in subjects with metabolic syndrome (MetS).
 Material and methods: This was a single centre, retrospective, comparative study done on patients with MetS in 100 in a tertiary care hospital over period of 18 months from October 2019 to March 2021. Enrolled patients underwent conventional ultrasonography (USG), point SWE (pSWE), fasting blood sugar, post-prandial blood sugar, glycosylated HbA1c, lipid profile, LFTs. Appropriate statistical tests were applied using SPSS v21 for analysis and p-value<0.05 was considered statistically significant.
 Results: Mean age was 55.8 (SD±15.34). Majority belonged to age group 51-65 years (33%). Grade 3 fatty liver (steatosis) on USG had 3.39 times independently (OR:3.39,p=0.043) more chance of having significant fibrosis or cirrhosis(F3-F4) by SWE over those who do not have fatty liver (steatosis) on USG. Those with 4 components of MetS had 6 times (OR:6.04,p=0.003) and those with 5 components had 13.7 (OR:13.768,p=0.001) times more chance of having significant fibrosis or cirrhosis(F3-F4) by SWE over those who have 3 components independently.
 Conclusion: Increasing number of components of MetS and steatosis (fatty liver grade) on USG were independently associated with higher grades of fibrosis by SWE.

Systematic Review with Meta-Analysis: Diagnostic Accuracy of Pro-C3 for Hepatic Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.

The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a biomarker of active fibrogenesis, in detecting significant fibrosis (F ≥ 2), advanced fibrosis (F ≥ 3), cirrhosis (F4) and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. A sensitive search of five databases was performed in July 2021. Studies reporting Pro-C3 measurements and liver histology in adults with NAFLD without co-existing liver diseases were eligible. Meta-analysis was conducted by applying a bivariate random effects model to produce summary estimates of Pro-C3 accuracy. From 35 evaluated reports, eight studies met our inclusion criteria; 1568 patients were included in our meta-analysis of significant fibrosis and 2058 in that of advanced fibrosis. The area under the summary curve was 0.81 (95% CI 0.77–0.84) in detecting significant fibrosis and 0.79 (95% CI 0.73–0.82) for advanced fibrosis. Our results support Pro-C3 as an important candidate biomarker for non-invasive assessment of liver fibrosis in NAFLD. Further direct comparisons with currently recommended non-invasive tests will demonstrate whether Pro-C3 panels can outperform these tests, and improve care paths for patients with NAFLD.

Correlation of secreted frizzled related protein-4 adipokin expression and expression of fatty liver changes under the conditions of a chronic experiment

The article highlights the results of a study of a new method for diagnosing non-alcoholic fatty liver disease in a living organism by determining the serum level of the marker Secreted frizzled related protein-4 (SFRP4) with histological confirmation of the results. In a chronic experiment, the parameters of two groups of experimental animals were studied: control and experimental, 15 rats each. The control (reference) group of animals was in the usual feed and drinking mode, the experimental received food with a high content of carbohydrates and fats. The results of biochemical blood tests and autopsy biomaterials on day 180 of the experiment indicated the presence of fatty changes in the liver in the experimental group of animals. The importance of circulating adipokine SFRP4 in the diagnosis of non-alcoholic fatty liver disease (NAFLD) has been confirmed. A histologically confirmed direct correlation of SFRP4 with the degree of liver fibrosis in NAFLD was revealed. The place of SFRP4 in the pathogenesis of non-alcoholic fatty liver damage is explained. It is noted that in case of successful extrapolation of the results of the study on the human body, information will become a successful solution to one of the most pressing problems of modern hepatology.

Free Triiodothyronine Is Associated With Hepatic Steatosis and Liver Stiffness in Euthyroid Chinese Adults With Non-Alcoholic Fatty Liver Disease

ObjectiveThe association between non-alcoholic fatty liver disease (NAFLD) and thyroid hormones in euthyroid subjects is unclear. We investigated the relationship between thyroid function and the severity of hepatic steatosis and liver fibrosis in a large cohort of euthyroid Chinese adults.MethodsA total of 3496 participants were enrolled. Liver ultrasonography was used to define the presence of NAFLD (n=2172) or the absence of NAFLD (n=1324). Anthropometric and biochemical measurements were made and thyroid function parameters including free triiodothyronine (FT3), free thyroxine (FT4), thyroid‐stimulating hormone (TSH) were measured. The severity of hepatic steatosis and liver stiffness was assessed by transient elastography.ResultsLevels of FT3 were significantly higher in the severe NAFLD group and moderate NAFLD group than in the mild NAFLD group (5.18 ± 0.58 vs 5.11 ± 0.57 vs 4.98 ± 0.60 pmol/L, P<0.001). Participants with F4 and F3 liver fibrosis had higher FT3 levels than those with F2 fibrosis (6.33 ± 0.39 vs 5.29 ± 0.48 vs 5.20 ± 0.50 pmol/L, P<0.001). However, FT4 and TSH levels did not correlate with hepatic steatosis or liver fibrosis severity. In addition, the proportions of participants with NAFLD (46.0% vs 63.1% vs 73.3%, P<0.001) and liver fibrosis (11.5% vs 18.6% vs 20.8%, P<0.001) increased as FT3 levels increased. Logistic regression analysis showed that FT3 levels were positively associated with the severity of hepatic steatosis and liver fibrosis presence, even after adjustment for metabolic risk factors including BMI. In non-obese participants, the FT3 level was an independently risk factor for the severity of hepatic steatosis.ConclusionsThere are positive associations of FT3 levels with the severity of hepatic steatosis and the presence of liver fibrosis in NAFLD with euthyroidism.

Growth differentiation factor-15 and the association between type 2 diabetes and liver fibrosis in NAFLD

BackgroundType 2 diabetes mellitus (T2DM) is a strong risk factor for liver fibrosis in non-alcoholic fatty liver disease (NAFLD). It remains uncertain why T2DM increases the risk of liver fibrosis. It has been suggested that growth differentiation factor-15 (GDF-15) concentrations increase the risk of liver fibrosis. We aimed to investigate (a) whether GDF-15 concentrations were associated with liver fibrosis and involved in the relationship between T2DM and liver fibrosis and (b) what factors linked with T2DM are associated with increased GDF-15 concentrations.MethodsNinety-nine patients with NAFLD (61% men, 42.4% T2DM) were studied. Serum GDF-15 concentrations were measured by electro-chemiluminescence immunoassay. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis. Regression modelling, receiver operator characteristic curve analysis and Sobel test statistics were used to test associations, risk predictors and the involvement of GDF-15 in the relationship between T2DM and liver fibrosis, respectively.ResultsPatients with NAFLD and T2DM (n = 42) had higher serum GDF-15 concentrations [mean (SD): 1271.0 (902.1) vs. 640.3 (332.5) pg/ml, p < 0.0001], and a higher proportion had VCTE assessed ≥F2 fibrosis (48.8 vs. 23.2%, p = 0.01) than those without T2DM. GDF-15 was independently associated with liver fibrosis (p = 0.001), and GDF-15 was the most important single factor predicting ≥F2 or ≥F3 fibrosis (≥F2 fibrosis AUROC 0.75, (95% CI 0.63–0.86), p < 0.001, with sensitivity, specificity, positive predictive (PPV) and negative predictive (NPV) values of 56.3%, 86.9%, 69.2% and 79.1%, respectively). GDF-15 was involved in the association between T2DM and ≥F2 fibrosis (Sobel test statistic 2.90, p = 0.004). Other factors associated with T2DM explained 60% of the variance in GDF-15 concentrations (p < 0.0001). HbA1c concentrations alone explained 30% of the variance (p < 0.0001).ConclusionsGDF-15 concentrations are a predictor of liver fibrosis and potentially involved in the association between T2DM and liver fibrosis in NAFLD. HbA1c concentrations explain a large proportion of the variance in GDF-15 concentrations.

404-P: Advanced Liver Fibrosis Is Associated with an Increased Risk of Chronic Kidney Disease in Patients with Type 2 Diabetes and NAFLD

Objectives: Nonalcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). However, the causal relationship between NAFLD and the development of CKD is uncertain, particularly in patients with type 2 diabetes. We aimed to investigate the association between the presence and severity of NAFLD and incident CKD in patients with type 2 diabetes. Research Design and Methods: In this longitudinal cohort study of patients with type 2 diabetes, 3,188 patients with preserved renal function were followed for the occurrence of incident CKD. NAFLD was defined as the presence of hepatic steatosis on ultrasonography without any other causes of chronic liver diseases. Advanced liver fibrosis of NAFLD was defined as NAFLD fibrosis score &amp;gt;0.675. CKD was defined as estimated glomerular filtration rate (eGFR) &amp;lt; 60 mL/min/1.73 m2. Results: At baseline, 1,729 (54.2%) patients had NAFLD, of whom 94 (5.4%) had advanced liver fibrosis. During the follow-up of 8.3 ± 3.6 years, 472 (14.8%) patients developed incident CKD, 220 (15.1%) in the non-NAFLD group, 226 (12.8%) in the hepatic steatosis alone group and 26 (27.7%) in the advanced liver fibrosis group. There was no increased risk of incident CKD in the NAFLD group compared with the non-NAFLD group (p = 0.79). However, among patients with NAFLD, advanced liver fibrosis was associated with an increased risk of CKD (adjusted hazard ratio [HR] 1.78 (95% confidence interval [CI] 1.14-2.76), p=0.011). Conclusions: Advanced liver fibrosis in NAFLD is independently associated with an increased risk of incident CKD in patients with type 2 diabetes. Disclosure D. Seo: None. Y. Cho: None. S. Ahn: None. S. Seo: None. S. Hong: None. Y. Lee: None. S. Kim: None. Funding National Research Foiundation (2017R1D-1A1B03034581)

Atherogenic dyslipidemia, but not hyperglycemia, is an independent factor associated with liver fibrosis in subjects with type 2 diabetes and NAFLD: a population-based study.

To investigate the prevalence and risks factors associated with the presence of liver fibrosis in subjects with nonalcoholic fatty liver disease (NAFLD) with and without type 2 diabetes mellitus (T2D). This study was part of a population-based study conducted in the Barcelona metropolitan area among subjects aged 18-75 years old. Secondary causes of steatosis were excluded. Moderate-to-advanced liver fibrosis was defined as a liver stiffness measurement (LSM) ≥ 8.0 kPa assessed by transient elastography. Among 930 subjects with NAFLD, the prevalence of moderate-to-advanced liver fibrosis was higher in subjects with T2D compared those without (30.8% vs 8.7%). By multivariable analysis, one of the main factors independently associated with increased LSM in subjects with NAFLD was atherogenic dyslipidemia but only in those with T2D. The percentage of subjects with LSM ≥ 8.0 kPa was higher in subjects with T2D and atherogenic dyslipidemia than in those with T2D without atherogenic dyslipidemia both for the cut-off point of LSM ≥8.0 kPa (45% vs 24% P = 0.002) and ≥13 kPa (13% vs 4% P = 0.020). No differences were observed in the prevalence of LSM ≥8.0 kPa regarding glycemic control among NAFLD-diabetic subjects. Factors associated with moderate-to-advanced liver fibrosis in NAFLD are different in subjects with and without T2D. Atherogenic dyslipidemia was associated with the presence of moderate-to-advanced liver fibrosis in T2D with NAFLD but not in non-diabetic subjects. These findings highlight the need for an active search for liver fibrosis in subjects with T2D NAFLD and atherogenic dyslipidemia.

Serum zinc level and hepatic fibrosis in patients with nonalcoholic fatty liver disease.

This study aimed to investigate the relationship between serum zinc level and hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). A cross-sectional study was conducted using nationally representative samples from the Korea National Health and Nutrition Examination Survey 2010. Significant hepatic fibrosis was defined as Fibrosis-4 (FIB-4) index>1.3. Zinc level was measured using inductively coupled plasma mass spectrometry. Univariable and multivariable logistic regression analyses were performed to assess risk factors for significant hepatic fibrosis in patients with NAFLD. A total of 300 patients with NAFLD were analyzed in this study. The mean serum zinc level was 139.8±29.9 μg/dL. FIB-4 index was significantly increased as the serum zinc level decreased (Adjusted correlation coefficient = -0.177, p = 0.003). Significant liver fibrosis was observed in 62 patients (21%). The multivariable analysis showed that significant liver fibrosis in NAFLD was associated with diabetes mellitus (odds ratio [OR], 3.25; 95% confidence interval [CI], 1.71-6.19; p<0.001), male (OR, 2.59; 95% CI, 1.31-5.12; p = 0.006), and zinc level <140 μg/dL (OR, 2.14; 95% CI, 1.16-3.94; p = 0.015). There was an inverse relationship between serum zinc level and FIB-4 index in NAFLD. Low levels of serum zinc were an independent risk factor for significant hepatic fibrosis in NAFLD.

The triglyceride-glucose index is associated with the severity of hepatic steatosis and the presence of liver fibrosis in non-alcoholic fatty liver disease: a cross-sectional study in Chinese adults

BackgroundThe triglyceride-glucose index (TyG) is a reliable predictor of non-alcoholic fatty liver disease (NAFLD). Its association with the severity of hepatic steatosis and liver fibrosis in NAFLD is poorly understood. This study evaluated the relationship between these factors in NAFLD.MethodsA total of 4784 participants who underwent ultrasonography were enrolled. Anthropometric and biochemical measurements were assessed. Participants with NAFLD were diagnosed by ultrasound. The degree of hepatic steatosis and liver stiffness was evaluated with transient elastography.ResultsThe TyG index was significantly correlated with the severity of hepatic steatosis and the presence of liver fibrosis in patients with NAFLD. TyG quartile values correlated with increasing prevalence of NAFLD (Q1 30.9%, Q2 53.3%, Q3 71.7%, and Q4 86.4%, P < 0.001) and with the presence of liver fibrosis (Q1 13.5%, Q2 17.6%, Q3 18.8%, and Q4 26.1%, P < 0.001). The AUROC for the TyG index to predict NAFLD was 0.761, resulting in a cut-off value of 8.7. However, the AUC value of the TyG index was 0.589 for liver fibrosis, which was insufficient to predict this condition. The adjusted odds of having hepatic steatosis or liver fibrosis were more strongly associated with TyG values compared with HOMA-IR.ConclusionThe TyG index is positively related to the severity of hepatic steatosis and the presence of liver fibrosis in NAFLD. The index also performed better than HOMA-IR.

Hepatocellular Carcinoma and Non-Alcoholic Fatty Liver Disease: A Step Forward for Better Evaluation Using Ultrasound Elastography.

Simple SummaryNon-alcoholic fatty liver disease (NAFLD) attracts a lot of attention, due to the increasing prevalence and progression to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Consequently, new non-invasive, cost-effective diagnostic methods are needed. This review aims to explore the diagnostic performance of ultrasound (US) elastography in NAFLD and NAFLD-related HCC, adding a new dimension to the conventional US examination—the liver stiffness quantification. The vibration controlled transient elastography (VCTE), and 2D-Shear wave elastography (2D-SWE) are effective in staging liver fibrosis in NAFLD. VCTE presents the upside of assessing steatosis through the controlled attenuation parameter. Hereby, we critically reviewed the elastography techniques for the quantitative characterization of focal liver lesions (FLLs), focusing on HCC: Point shear wave elastography and 2D-SWE. 2D-SWE presents a great potential to differentiate malignant from benign FLLs, guiding the clinician towards the next diagnostic steps. As a disease-specific surveillance tool, US elastography presents prognostic capability, improving the NAFLD-related HCC monitoring.The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population prompts for a quick response from physicians. As NAFLD can progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC), new non-invasive, rapid, cost-effective diagnostic methods are needed. In this review, we explore the diagnostic performance of ultrasound elastography for non-invasive assessment of NAFLD and NAFLD-related HCC. Elastography provides a new dimension to the conventional ultrasound examination, by adding the liver stiffness quantification in the diagnostic algorithm. Whilst the most efficient elastographic techniques in staging liver fibrosis in NAFLD are vibration controlled transient elastography (VCTE) and 2D-Shear wave elastography (2D-SWE), VCTE presents the upside of assessing steatosis through the controlled attenuation parameter (CAP). Hereby, we have also critically reviewed the most important elastographic techniques for the quantitative characterization of focal liver lesions (FLLs), focusing on HCC: Point shear wave elastography (pSWE) and 2D-SWE. As our paper shows, elastography should not be considered as a substitute for FLL biopsy because of the stiffness values overlap. Furthermore, by using non-invasive, disease-specific surveillance tools, such as US elastography, a subset of the non-cirrhotic NAFLD patients at risk for developing HCC can be detected early, leading to a better outcome. A recent ultrasomics study exemplified the wide potential of 2D-SWE to differentiate benign FLLs from malignant ones, guiding the clinician towards the next steps of diagnosis and contributing to better long-term disease surveillance.

COVID-19 and non-alcoholic fatty liver disease: Two intersecting pandemics.

BackgroundInitial evidence from China suggests that most vulnerable subjects to COVID‐19 infection suffer from pre‐existing illness, including metabolic abnormalities. The pandemic characteristics and high‐lethality rate of COVID‐19 infection have raised concerns about interactions between virus pathobiology and components of the metabolic syndrome.MethodsWe harmonized the information from the recent existing literature on COVID‐19 acute pandemic and mechanisms of damage in non‐alcoholic fatty liver disease (NAFLD), as an example of chronic (non‐communicable) metabolic pandemic.ResultsCOVID‐19‐infected patients are more fragile with underlying metabolic illness, including hypertension, cardiovascular disease, type 2 diabetes, chronic lung diseases (e.g. asthma, chronic obstructive pulmonary disease and emphysema) and metabolic syndrome. During metabolic abnormalities, expansion of metabolically active fat ('overfat condition') parallels chronic inflammatory changes, development of insulin resistance and accumulation of fat in configuring NAFLD. The deleterious interplay of inflammatory pathways chronically active in NAFLD and acutely in COVID‐19‐infected patients, can explain liver damage in a subgroup of patients and might condition a worse outcome in metabolically compromised NAFLD patients. In a subgroup of patients with NAFLD, the underlying liver fibrosis might represent an additional and independent risk factor for severe COVID‐19 illness, irrespective of metabolic comorbidities.ConclusionsNAFLD can play a role in the outcome of COVID‐19 illness due to frequent association with comorbidities. Initial evidences suggest that increased liver fibrosis in NAFLD might affect COVID‐19 outcome. In addition, long‐term monitoring of post‐COVID‐19 NAFLD patients is advisable, to document further deterioration of liver damage. Further studies are required in this field.

Increased serum selenium levels are associated with reduced risk of advanced liver fibrosis and all-cause mortality in NAFLD patients: National Health and Nutrition Examination Survey (NHANES) III

Introduction and objectivesSelenium supplementation has been shown to have therapeutic value in chronic liver disease. We aimed to investigate the association between serum selenium, severity of liver fibrosis, and mortality in patients with Nonalcoholic Fatty Liver Disease (NAFLD). Patients or material and methodsA total of 33,944 patients were identified from the Third National Health and Nutrition Examination Survey. NAFLD was diagnosed by hepatic ultrasound after the exclusion of other forms of liver diseases. The severity of liver fibrosis was determined by NAFLD Fibrosis Score >0.676. Multivariate logistic regression analysis was used to investigate the relationship between serum selenium level and liver fibrosis. Association between serum selenium and all-cause mortality in NAFLD patients was also evaluated. ResultsMultivariate logistic regression analysis demonstrated odds ratio of advanced liver fibrosis (NFS > 0.676) was significantly reduced with increasing serum selenium levels; OR 0.55, [95% CI 0.32−0.94] in the highest selenium quartile. On stratification analysis, the following populations had a significantly reduced risk of advanced liver fibrosis: non-Hispanic white = OR 0.41 [0.24,0.68]; female = OR 0.32 [0.15−0.66] and age >47 = OR 0.47 [0.28−0.79]. The relationship was significant regardless of BMI as noted by BMI ≤ 30 Kg/m2= OR 0.42 [0.19−0.91] and BMI > 30 Kg/m2=OR 0.52 [0.28−0.97]. Hazard ratio for all-cause mortality was HR 0.72 [0.56−0.95]. ConclusionsThe risk of advanced liver fibrosis is inversely associated with serum selenium levels, particularly in older patients, Caucasians, and females. All-cause mortality decreased with increased selenium levels. Selenium may play a role in the prevention of liver fibrosis in NAFLD.

Decrease in fasting insulin secretory function correlates with significant liver fibrosis in Japanese non-alcoholic fatty liver disease patients.

Background and AimNon‐alcoholic fatty liver disease (NAFLD) is typically associated with metabolic syndrome and diabetes, and insulin resistance is involved in its pathogenesis. However, the relationship between insulin secretion and NAFLD is unclear. We aimed to characterize the relationship between fasting insulin secretory function (ISF), evaluated using the homeostatic model assessment‐beta cell function (HOMA‐β) and the severity of fibrosis during NAFLD.MethodsA‐β was calculated in 188 patients with biopsy‐confirmed NAFLD, and the correlations between Log HOMA‐β and clinical parameters, including hepatic fibrosis, were calculated.ResultsLog HOMA‐β was significantly lower in NAFLD patients with significant fibrosis (stages 2–4) than in those in the early stages (stages 0–1) (median [interquartile range]) (2.1 [1.9–2.4] vs 2.0 [1.8–2.2], P = 0.04). The prevalence of significant fibrosis decreased with increasing Log HOMA‐β: it was 59.2% in participants with low ISF (Log HOMA‐β < 1.85), 43.6% in those with intermediate ISF (1.85 ≤ Log HOMA‐β < 2.25), and 68.0% in those with high ISF (Log HOMA‐β ≥ 2.25). Patients with lower Log HOMA‐β had lower current body mass index (BMI), BMI at 20 years of age, and peak lifetime BMI than patients with intermediate or high Log HOMA‐β.ConclusionsFasting ISF decreased alongside the development of liver fibrosis in NAFLD, suggesting that an impaired β cell function has a characteristic finding of significant liver fibrosis in relatively nonobese Japanese patients.

Analysis of Liver Fibrosis Degree with APRI Score and FIB-4 Index on Patients with Non-Alcoholic Fatty Liver Disease

Liver fibrosis is the accumulation of Extracellular Matrix Protein (EMP) scar tissue after acute or chronic liver injury. Liverbiopsy is the gold standard test for evaluating liver fibrosis in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). Thisdiagnostic method is invasive, painful, and complicated in rare cases; thus the noninvasive methods such as laboratory testsand radiology had been proposed to assess liver fibrosis in NAFLD and are expected to overcome the limitations of liverbiopsy. This method consists of aspartate Aminotransferase to the Platelet Ratio Index (APRI) and fibrosis-4 (FIB-4).Thisresearch was retrospective cross-sectional performed at Dr. Wahidin Sudirohusodo Hospital Makassar involving 63 subjectsfrom January to June 2018. The correlated variables were presented in categorical and numerical data and the Pearsoncorrelation test was used to determine the compatibility of APRI score and FIB-4 index with Fibroscan result in patientswith NAFLD. A highly significant positive correlation (p &lt;0.001) was found between APRI score and Fibroscan (correlationvalue = 45.8%), APRI score and FIB-4 index (correlation value = 91.8%), FIB-4 index and Fibroscan (correlationvalue = 47.6%). The score of Aminotransferase to platelet ratio index score and FIB-4 index could be an alternative methodinstead of a liver biopsy to predict the degree of fibrosis in patients with NAFLD.

When the liver gets stiff, the tough get moving.

Liver stiffness measurement (LSM) by FibroScan-determined transient elastography is a noninvasive approach to estimate liver fibrosis severity. In non-alcoholic fatty liver disease (NAFLD), advanced liver fibrosis is excluded by normal liver stiffness, but a wide range of cutoffs have been used to predict advanced liver fibrosis or cirrhosis. This may be partly because steatosis (measured by controlled attenuation parameter [CAP]) contributes to liver stiffness and also because LSM fluctuates in NAFLD. In a recent pivotal study, one-third of patients with liver stiffness >12.0kPa showed reversal after 4-6months; these cases did not have advanced liver fibrosis on biopsy. We performed serial FibroScans 6-36months apart in 73 NAFLD patients, 38 with LSM>10kPa at entry. Those who lost ≥1kg of weight (n=31) significantly reduced liver stiffness (3.6±6.1 vs 0.53±4.1kPa, P<0.05) and CAP score (39±63dB/m of loss vs 24±65dB/m of gain, P<0.05) compared with those who did not (n=29). Patients who reported increased physical activity (n=25) also reduced liver stiffness (3.6±6 vs 0.35±6kPa) and CAP (20±71dB/m of loss vs 32±71dB/m of gain). Overall, those with improved LSM were significantly more likely to have lost weight and/or improved physical activity. These effects of lifestyle adjustments partly explain why a single measurement of 12.0kPa is not a reliable cutoff for advanced liver fibrosis in NAFLD. In addition to repeating the study after 6-12months, documentation of response to lifestyle advice and weight reduction should be determined before assuming any cutoff indicates advanced liver fibrosis. Despite this reservation about diagnostic accuracy, we consider that measurement of liver stiffness and CAP score serve to motivate patients to enact lifestyle modifications that can improve NAFLD severity.

Non-invasive tests for liver fibrosis in NAFLD: Creating pathways between primary healthcare and liver clinics.

Despite affecting around one-fourth of the general population worldwide, non-alcoholic fatty liver disease (NAFLD) remains a largely under-recognized disease in primary healthcare, with not more than 10% of patients diagnosed with NAFLD referred to specialists. The main challenge in clinical practice is the identification of those with advanced liver fibrosis or cirrhosis, as they are at the greatest risk of developing complications. Liver biopsy appears to be an unrealistic and unsuitable option because of the large number of high-risk patients and the well-known limitations of this technique. This has favoured the development of non-invasive tests, which have been an area of intensive research in the past decade. Transient elastography, FIB-4 and the NAFLD fibrosis score are the most extensively used and best validated tests, with summary AUROC values for detecting advanced fibrosis in NAFLD patients of 0.88, 0.84 and 0.84 respectively. Although much work remains to be done to establish cost-effective strategies for the screening for advanced fibrosis, the sequential use of non-invasive tests (serum biomarkers, then measurement of liver stiffness using transient elastography) appears to be the most promising strategy. The next step is to establish effective pathways in primary healthcare and/or diabetes clinics where most NAFLD patients are seen, to identify those who need to be referred to liver clinics for further assessment.