Advanced Nonalcoholic Fatty Liver Disease Research Articles

Shear Wave Elastography Reveals a High Prevalence of NAFLD-related Fibrosis even in Type 1 Diabetes.

The association between type 2 diabetes mellitus (T2DM) and advanced stages of non-alcoholic fatty liver disease is well known. Some studies indicate a relevant prevalence also in type 1 diabetes mellitus (T1DM), but so far there is only limited data. To determine the prevalence of non-alcoholic fatty liver disease (NAFLD)-related liver fibrosis in individuals with T1DM and compare to those with type 2 diabetes. Diabetic patients from a single diabetes care centre were screened for liver fibrosis by sonographic shear wave elastography (SWE). In addition, all patients received laboratory evaluation including non-alcoholic fatty liver fibrosis score and Fibrosis-4 Index. Three hundred and forty patients were included in the study, of these, 310 received SWE. Overall 254 patients (93 with type 1 and 161 with type 2 diabetes) had reliable measurements and were included in the final analysis. In patients with type 1 diabetes, the prevalence of NAFLD-related liver fibrosis was 16-21%, depending on the method of detection. Significant liver fibrosis was observed in 30-46% of patients with type 2 diabetes. Our data revealed an unexpectedly high prevalence of NAFLD-related liver fibrosis in patients with type 1 diabetes. To our knowledge, this is one of the first studies using SWE to diagnose advanced NAFLD in type 1 diabetes in a non-preselected cohort. Considering the findings of our study, regular screening for hepatic complications must be recommended for all diabetic patients, even for those with type 1 diabetes.

Decompensation in Advanced Nonalcoholic Fatty Liver Disease May Occur at Lower Hepatic Venous Pressure Gradient Levels Than in Patients With Viral Disease

Portal hypertension is the strongest predictor of hepatic decompensation and death in patients with cirrhosis. However, its discriminatory accuracy in patients with nonalcoholic fatty liver disease (NAFLD) has been challenged because hepatic vein catheterization may not reflect the real portal vein pressure as accurately as in patients with other etiologies. We aimed to evaluate the relationship between hepatic venous pressure gradient (HVPG) and presence of portal hypertension-related decompensation in patients with advanced NAFLD (aNAFLD). Multicenter cross-sectional study included 548 patients with aNAFLD and 444 with advanced RNA-positive hepatitis C (aHCV) who had detailed portal hypertension evaluation (HVPG measurement, gastroscopy, and abdominal imaging). We examined the relationship between etiology, HVPG, and decompensation by logistic regression models. We also compared the proportions of compensated/decompensated patients at different HVPG levels. Both cohorts, aNAFLD and aHVC, had similar baseline age, gender, Child-Pugh score, and Model for End-Stage Liver Disease score. Median HVPG was lower in the aNAFLD cohort (13 vs 15 mmHg) despite similar liver function and higher rates of decompensation in aNAFLD group (32% vs 25%; P= .019) than in the aHCV group. For any of the HVPG cutoff analyzed (<10, 10-12, or 12 mmHg) the prevalence of decompensation was higher in the aNAFLD group than in the aHCV group. Patients with aNAFLD have higher prevalence of portal hypertension-related decompensation at any value of HVPG as compared with aHCV patients. Longitudinal studies aiming to identify HVPG thresholds able to predict decompensation and long-term outcomes in aNAFLD population are strongly needed.

Disentangling the Progression of Non-alcoholic Fatty Liver Disease in the Human Gut Microbiota.

Gut microbiome dysbiosis has been known to be associated with all stages of non-alcoholic fatty liver disease (NAFLD), but questions remain about microbial profiles in progression and homogeneity across NAFLD stages. We performed a meta-analysis of three publicly shotgun datasets and built predictive models to determine diagnostic capacity. Here, we found consistently microbiome shifts across NAFLD stages, of which co-occurrence patterns and core sets of new biomarkers significantly correlated with NAFLD progression were identified. Machine learning models that are able to distinguish patients with any NAFLD stage from healthy controls remained predictive when applied to patients with other NAFLD stages, suggesting the homogeneity across stages once again. Focusing on species and metabolic pathways specifically associated with progressive stages, we found that increased toxic metabolites and decreased protection of butyrate and choline contributed to advanced NAFLD. We further built models discriminating one stage from the others with an average of 0.86 of area under the curve. In conclusion, this meta-analysis firmly establishes generalizable microbiome dysbiosis and predictive taxonomic and functional signatures as a basis for future diagnostics across NAFLD stages.

Are Serum Levels of Nuclear Factor Kappa B and Forkhead Box Protein P3 in Patients with Non-Alcoholic Fatty Liver Disease Related to Severity of Fibrosis?

BACKGROUND Inflammation has a significant impact on the development and progression of fatty liver diseases.In this study, we aimed to investigate the relation between serum levels of nuclear factor kappa B (NFkB) and Forkhead box protein P3 (FOXP3)with fibrosis severity among patients with non-alcoholic fatty liver disease(NAFLD). METHODS In a prospective study, the patients suspicios of havingfatty liver were enrolled. The exclusion criteria lack of viral hepatitis, autoimmune hepatitis, Wilson's or other known liver diseases,history of liver or biliary surgery,bariatric surgery, and medications that influence liver metabolism. The participantsunderwent liver fibroscan. According to liver fibrosis, the patients weredivided into two groups; 1)fibrosis less than 7.2 KP,2)advanced NAFLD, fibrosis ≥7.3 KP. A10 cc fasting blood sample was taken from each patient for laboratory assessments.The variables between the two groups were compared using Chi-square or Fisher's exact test.The independence of cytokines was assessed by a logistic regression test. RESULTS Totally 90 patients were enrolled.The mean age was 42.21 ± 11 years. Of them, 50 and 47 participants were allocated to groups 1 and 2, respectively. In the univariate analysis, we revealed asignificant difference between age, body mass index (BMI), fasting blood glucose, liver enzymes, total cholesterol, andtriglyceride levels. Also, there was a significant difference betweenthe levels of NFKB and FOXP3 in group one compared with group two of the participants,as FOXP3(9.17 ± 10.0 vs. 18.63 ± 12.9; p < 0.001) and NFKB (1.70 ± 1.70; p < 0.01). After excluding the confounding factors, we observed a significant association between fibrosis level and cytokine levels in logistic regression. CONCLUSION Serum levels of NFKB and FOXP3 increased by advancing liver fibrosis in patients with NAFLD.This is an independent association. The identification of intermediary regulatory factors would be necessary.

Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States

Recently, international experts proposed redefining non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD), based on modified criteria. It is suspected that outcomes such as mortality may differ for these clinical entities. We studied the impact of MAFLD and NAFLD on all-cause and cause-specific mortality in US adults. We analyzed data from 7,761 participants in the Third National Health and Nutrition Examination Survey and their linked mortality through 2015. NAFLD was diagnosed by ultrasonographic evidence of hepatic steatosis without other known liver diseases. MAFLD was defined based on the criteria proposed by an international expert panel. The Cox proportional hazard model was used to study all-cause mortality and cause-specific mortality between MAFLD and NAFLD, with adjustments for known risk factors. During a median follow-up of 23 years, individuals with MAFLD had a 17% higher risk of all-cause mortality (hazard ratio [HR] 1.17; 95% CI 1.04-1.32). Furthermore, MAFLD was associated with a higher risk of cardiovascular mortality. NAFLD per se did not increase the risk of all-cause mortality. Individuals who met both definitions had a higher risk of all-cause mortality (HR 1.13, 95% CI 1.00-1.26), while individuals who met the definition for MAFLD but not NAFLD had a 1.7-fold higher risk of all-cause mortality (HR 1.66, 95% CI 1.19-2.32). Estimates for all-cause mortality were higher for those with advanced fibrosis and MAFLD than for those with advanced fibrosis and NAFLD. In this US population-based study, MAFLD was associated with an increased risk of all-cause mortality, while NAFLD demonstrated no association with all-cause mortality after adjusting for metabolic risk factors. Our findings provide further support for the idea that non-alcoholic fatty liver disease (NAFLD) is a part of a broader multi-system disease that also includes obesity, diabetes, high blood pressure, and high cholesterol. Therefore, re-defining NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD) may help improve our understanding of predictors that increase the risk of death.

Omega-3 phospholipids and obesity-associated NAFLD: Potential mechanisms and therapeutic perspectives.

Prevalence of non-alcoholic fatty liver disease (NAFLD) increases in line with obesity and type 2 diabetes, and there is no approved drug therapy. Polyunsaturated fatty acids of n-3 series (omega-3) are known for their hypolipidaemic and anti-inflammatory effects. Existing clinical trials suggest varying effectiveness of triacylglycerol- or ethyl ester-bound omega-3 in the treatment of NAFLD, without affecting advanced stages such as non-alcoholic steatohepatitis. Preclinical studies suggest that the lipid class used to supplement omega-3 may determine the extent and nature of their effects on metabolism. Phospholipids of marine origin represent an alternative source of omega-3. The aim of this review is to summarise the available evidence on the use of omega-3 phospholipids, primarily in obesity-related NAFLD, and to outline perspectives of their use in the prevention/treatment of NAFLD. A PubMed literature search was conducted in May 2021. In total, 1088 articles were identified, but based on selection criteria, 38 original papers were included in the review. Selected articles describing the potential mechanisms of action of omega-3 phospholipids have also been included. Preclinical evidence clearly indicates that omega-3 phospholipids have strong antisteatotic effects in the liver, which are stronger compared to omega-3 administered as triacylglycerols. Multiple mechanisms are likely involved in the overall antisteatotic effects, involving not only the liver but also adipose tissue and the gut. Robust preclinical evidence for strong antisteatotic effects of omega-3 phospholipids in the liver should be confirmed in clinical trials. Further research is needed on the possible effects of omega-3 phospholipids on advanced NAFLD.

A clinical model to predict fibrosis on liver biopsy in paediatric subjects with nonalcoholic fatty liver disease.

The incidence of nonalcoholic fatty liver disease (NAFLD) in children is rapidly increasing. Liver fibrosis is a poor prognostic feature that independently predicts cirrhosis. The time that intercedes the first medical encounter and biopsy is rate-limiting to multi-modal treatment. This study aimed to identify non-invasive parameters to predict advanced NAFLD and fibrosis. We conducted a single-center, retrospective 10-year analysis of 640 paediatric patients who underwent liver biopsy. 55 patients, age 3-21 years, had biopsy-confirmed NAFLD. We assessed primary outcomes, NAFLD activity score (NAS) and fibrosis scores, against non-invasive parameters by linear regression, by using binary cutoff values, and by a multivariate logistic regression fibrosis prediction model. NAS correlated with platelets and female sex. Fibrosis scores correlated with platelet counts, gamma glutamyl transferase (GGT), and ultrasound shear wave velocity. 25-hydroxy-vitamin D and GGT differentiated mild versus moderate-to-advanced fibrosis. Our multivariate logistical regression model-based scoring system predicted F2 or higher (parameters: BMI%, vitamin D, platelets, GGT), with sensitivity and specificity of 0.83 and 0.95 (area under the ROC curve, 0.944). We identify a clinical model to identify high-risk patients for expedited biopsy. Stratifying patients to abbreviate time-to-biopsy can attenuate delays in aggressive therapy for high-risk patients.

Feasibility of a Novel Nonhuman Primate Model of Age-Related Nonalcoholic Fatty Liver Disease

The objective of the proposed study is to investigate the feasibility of the marmoset as an animal model to study age-associated nonalcoholic fatty liver disease (NAFLD). This chronic liver disease includes a spectrum of disorders ranging from increased triglyceride accumulation in the liver or hepatic steatosis to the more severe inflammatory form nonalcoholic steatohepatitis that can lead to cirrhosis and even hepatocellular carcinoma in individuals who do not have a history of alcohol abuse. Aging increases the prevalence of NAFLD and is strongly associated with the progression and severity of this disease. End-stage hepatic failure and liver cancer resulting from advanced NAFLD are leading indications for liver transplantation enhancing the burden on our healthcare systems. Accumulating clinical evidence also suggests that patients with NAFLD have a higher prevalence of cardiovascular disease. Pathogenetic mechanisms involved in the development and progression of NAFLD are poorly understood and as such, there is a lack of effective therapies. The common marmoset is a relatively short-lived non-human primate that recapitulates many of the physiological changes that occur in human aging. We hypothesized an age-associated increase in hepatic steatosis and alterations in serum lipid profile in the marmoset model. An increase in triglyceride levels and oil red o staining in liver tissues of old marmosets compared to young animals was observed suggesting an age-associated increase in hepatic steatosis in marmosets as observed in humans. Lipidomic studies were also performed using blood samples from male and female marmosets to investigate age-associated changes in specific lipid species, which are characteristic of aberrant lipid metabolism. Analysis of the results revealed significant decreases in several phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin species in the plasma of old marmosets compared to young marmosets. We are now performing studies to determine whether the observed changes in different lipid species could influence the development of cardiovascular disease and provide new insights underlying the mechanisms of NAFLD development with aging.

Both Elafibranor and Liraglutide Improve NAFLD / NASH but Affect Differentially the Hepatic Lipidome and Metabolome in a Diet-Induced Obese and Biopsy-Confirmed Mouse Model of NASH

Treatment of Nonalcoholic fatty liver disease (NAFLD) constitutes an unmet clinical need owing to the relatively limited efficacy of both novel and readily available metabolic medications, thus warranting pathobiological investigations on the mechanisms of single or combination regimens. In this context, our study aimed to assess and compare whether and how liraglutide, a glucagon-like peptide-1 receptor agonist, and elafibranor, a dual peroxisome proliferator-activated receptor alpha-delta agonist, may affect hepatic histology and metabolipidomic fingerprints in a model of advanced NAFLD. Male C57BL/6JRj mice with biopsy-confirmed hepatosteatosis and fibrosis induced by AMLN diet (40% fat with 20% trans-fat, 2% cholesterol and 22% fructose) were randomized to receive for 12 weeks: a) Liraglutide (0.4 mg/kg/d s.c.), b) Elafibranor (30 mg/kg/d p.o.), c) vehicle. Metabolic indices, liver function markers, liver pathology, and metabolomics/lipidomics were assessed at study completion. Both drugs markedly reduced body weight and fat percentage (p-value <0.001), and improved glucose tolerance and insulin sensitivity, as indicated by oral glucose and intraperitoneal insulin tolerance tests. Hepatic lipid content was downregulated under both treatments (p-value <0.001), especially under elafibranor, which also elevated liver weight in contrast with liraglutide (p-value vs liraglutide <0.001). NAFLD activity score (pre-to-post) and its histological components were substantially improved (mean difference ± standard error of mean: -1.4 ± 0.3 for liraglutide; -2.0 ± 0.2 for elafibranor), with elafibranor demonstrating a more robust anti-steatotic effect vs liralgutide (p-value <0.01) as well as anti-fibrotic effects (-0.5 ± 0.1). Liraglutide also limited the immunohistochemical expression of pro-inflammatory markers of Kupffer and hepatic stellate cell function (Galectin-3, Collagen type I alpha 1, and alpha-smooth muscle actin). In the omics analysis, elafibranor profoundly ameliorated the hepatic lipidome by diminishing the concentrations of glyceride species, increasing phospholipids and carnitine metabolites, and modifying key regulators of fatty acid oxidation, inflammation, and oxidative stress, including metabolites of methionine, glutathione, and pantothenate. Liraglutide significantly affected bile acid and carbohydrate metabolism by restoring the concentrations of metabolically beneficial primary and secondary bile acids, glycogen metabolism by-products, and pentoses, thus probably driving glycogen utilization-turnover and nucleic acid synthesis. Thus, liraglutide and elafibranor diverge in their mechanistic treatment of advanced NAFLD pathology, indicated by their robust but differential regulation of the hepatic metabolipidome. These findings support their combinatory therapeutic evaluation in future studies.

Association between the soluble receptor for advanced glycation end products (sRAGE) and NAFLD in participants in the Atherosclerosis Risk in Communities Study

BackgroundInflammation is key in the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) – a common progressive liver disease. The soluble receptor for advanced glycation end products (sRAGE) attenuates inflammatory signaling; low levels of sRAGE are correlated with increased inflammation. AimWe sought to describe associations between sRAGE and NAFLD. MethodsWe conducted a cross-sectional analysis of 1088 Atherosclerosis Risk in Communities (ARIC) Study participants and used logistic regression to investigate the associations between sRAGE and NAFLD defined by elevated liver enzymes and fibrosis score. ResultsIn this community-based sample (n = 1,088, mean age 56 years, 61% female, 78% Caucasian), persons in the lowest vs. highest quartile of sRAGE had significantly higher odds of elevated ALT (OR 2.82, 95% CI 1.18-6.76) but not elevated AST (OR 1.16, 95% CI 0.45-2.99); persons in the lowest vs. highest quartile had significantly lower odds of elevated FIB-4 index (OR 0.56, 95% CI 0.37-0.84). ConclusionsWe found an inverse cross-sectional association between sRAGE and liver inflammation; this is consistent with prior studies linking low sRAGE to inflammatory states. However, we observed a direct association between sRAGE and fibrosis. Our findings suggest that sRAGE is dynamic in NAFLD and patterns may vary with different stages of disease.

Insulin Resistance and Non-Alcoholic Fatty Liver Disease in Premenopausal Women with Metabolic Syndrome.

It is suggested that estrogen protects premenopausal women against non-alcoholic fatty liver disease. From another perspective, the relation between metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) is bidirectional. Role of insulin resistance (IR) in NAFLD continues to be a matter of debate. The present study aimed to assess the relation between IR and NAFLD in premenopausal women with MetS. The study included 51 premenopausal women with MetS. In addition, there were 40 age-matched healthy controls. All participants were subjected to careful history taking and thorough clinical examination. Performed laboratory investigations included fasting blood glucose, fasting insulin, lipid profile, and liver functions. Calculation of IR was achieved by the Homeostasis Model Assessment (HOMA-IR). NAFLD was graded into three grades according to findings of abdominal ultrasound. Patients had significantly higher BMI, SBP, DBP, FBG, fasting insulin, HOMA-IR, total cholesterol, triglycerides, and LDL levels when compared with controls. They also had significantly lower HDL levels in comparison to controls. Moreover, they have more advanced grades of NAFLD in contrast to controls. Comparison between patients with various grades of NAFLD regarding the clinical data revealed significant increase of fasting insulin and HOMA-IR levels with advancing NAFLD grade. Using multivariate regression analysis, HOMA-IR was an independent predictor of advanced NAFLD grade. In conclusion, the present study documented a combined inter-relation between MetS, IR, and NAFLD in premenopausal women with MetS. IR is correlated with NAFLD grade.

Validating candidate biomarkers for different stages of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic condition caused by the accumulation of fat in the liver. NAFLD may range from simple steatosis to advanced cirrhosis, and affects more than 1 billion people around the world. To date, there has been no effective treatment for NAFLD. In this study, we evaluated the expression of 4 candidate NAFLD biomarkers to assess their possible applicability in the classification and treatment of the disease.Twenty-six obese subjects, who underwent bariatric surgery, were recruited and their liver biopsies obtained. Expression of 4 candidate biomarker genes, PNPLA3, COL1A1, PPP1R3B, and KLF6 were evaluated at gene and protein levels by RT-qPCR and enzyme-linked immunosorbent assay (ELISA), respectively.A significant increase in the levels of COL1A1 protein (P = .03) and PNPLA3 protein (P = .03) were observed in patients with fibrosis-stage NAFLD compared to that in patients with steatosis-stage NAFLD. However, no significant differences were found in abundance of PPP1R3B and KLF6 proteins or at the gene level for any of the candidate.This is the first study, to our knowledge, to report on the expression levels of candidate biomarker genes for NAFLD in the Saudi population. Although PNPLA3 and PPP1R3B had been previously suggested as biomarkers for steatosis and KLF6 as a possible marker for the fibrosis stage of NAFLD, our results did not support these findings. However, other studies that had linked PNPLA3 to fibrosis in advanced NAFLD supported our current finding of high PNPLA3 protein in patients with fibrosis. Additionally, our results support COL1A1 protein as a potential biomarker for the fibrosis stage of NAFLD, and indicate its use in the screening of patients with NAFLD. Further studies are required to validate the use of COL1A1 as a biomarker for advanced NAFLD in a larger cohort.

Association of worsening of nonalcoholic fatty liver disease with cardiometabolic function and intestinal bacterial overgrowth: A cross-sectional study

Non-alcoholic fatty liver disease (NAFLD) has been associated with small bowel bacterial overgrowth (SIBO) and cardiometabolic dysfunction. This cross-sectional study aimed to evaluate the cardio-metabolic parameters and SIBO in patients with different degrees of hepatic fibrosis estimated by NAFLD fibrosis score (NFS). Subjects (n = 78) were allocated to three groups: Healthy control (n = 30), NAFLD with low risk of advanced fibrosis (NAFLD-LRAF, n = 17) and NAFLD with a high risk of advanced fibrosis (NAFLD-HRAF, n = 31). Anthropometrics, blood pressure, electrocardiogram and heart rate variability (HRV) were evaluated. Only the NAFLD-LRAF and NAFLD-HRAF groups were submitted to blood biochemical analysis and glucose hydrogen breath tests. The NAFLD-HRAF group had higher age and body mass index when compared to the control and NAFLD-LRAF groups. The prevalence of SIBO in the NAFLD group was 8.33%. The low frequency/high-frequency ratio (LF/HF ratio) was augmented in NAFLD-LRAF (p < 0.05) when compared with control group. NAFLD-HRAF group had a wide QRS complex (p < 0.05) and reduced LF/HF ratio (p < 0.05) compared to the control and NAFLD-LRAF groups. Serum levels of albumin and platelets were more reduced in the NAFLD-HRAF subjects (p < 0.05) than in the NAFLD-LRAF. NAFLD impairs cardiac autonomic function. Greater impairment was found in subjects with a worse degree of hepatic fibrosis estimated by NFS. Hypoalbuminemia and thrombocytopenia were higher in subjects with a worse degree of hepatic fibrosis, whereas prevalence of SIBO positive was similar between the groups.

External Validation of Four Point-of-Care Noninvasive Scores for Predicting Advanced Hepatic Fibrosis in a Predominantly Hispanic NAFLD Population.

The development of point-of-care biomarkers of disease has become a major focus of interest in nonalcoholic fatty liver disease (NAFLD). The NAFLD fibrosis score (NFS), BARD, FIB-4, and aspartate aminotransferase-to-platelet ratio index (APRI) are commonly used for advanced NAFLD fibrosis prediction. However, the performance of these scores among in a predominantly Hispanic patient population, a population with the highest prevalence of NAFLD, has not been examined. We performed a retrospective study among patients with histologically confirmed and staged NAFLD at the Ben Taub General Hospital, Houston, Texas, to externally validate four noninvasive advanced fibrosis prediction scores. Their discriminatory ability was assessed using the area under the receiver operating characteristic curve (AUROC). Sensitivity, specificity, positive, and negative predictive values were calculated. We included 99 NAFLD patients, of whom 37 (37.4%) had advanced fibrosis. The cohort was predominantly Hispanic (73.7%). The AUROC for detecting advanced fibrosis were: NFS 0.79 (95% confidence interval, 0.69-0.88), BARD 0.76 (0.67-0.86), FIB-4 0.77 (0.68-0.87), and APRI 0.70 (0.59-0.81). Using the low cutoff for the NFS (- 1.455) had the highest sensitivity (81.1%) and the highest negative predictive value (85.4%) among the overall study population. Noninvasive scores for advanced NAFLD fibrosis have moderate discriminatory ability in Hispanic patients with NFS having a small advantage. The AUROCs of these scores were similar to those reported in Caucasian populations. However, they had uniformly lower negative predictive values among our predominantly Hispanic study population, suggesting that they are not reliable for ruling out advanced fibrosis among this high-risk population.

Optimizing patients with non-alcoholic fatty liver disease pre-transplant.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries. Non-alcoholic steatohepatitis (NASH), which is the progressive counterpart of the disease, is becoming the leading indication for liver transplantation in North America. Owing to the lack of symptoms, NASH is often an incidental diagnosis, resulting in a significant proportion of patients being diagnosed when advanced liver disease has already developed. NAFLD has recently been characterized as the hepatic manifestation of metabolic syndrome. Consequently, it is a multisystem disease that often co-exists with several other conditions, such as obesity, diabetes, cardiovascular diseases, and extra-hepatic malignancy, which have an impact on selection of transplant recipients. The complexity of diagnostic approach, need for multidisciplinary clinical management, and lack of a specific treatment further complicate the picture of this extremely prevalent liver condition. NAFLD patients with advanced liver disease should be considered for early referral to liver transplant clinics for careful metabolic and cardiovascular risk stratification because they have worse survival rates after liver transplantation than other patients with chronic liver disease. Early referral will also facilitate optimization of metabolic comorbidities before proceeding with transplantation. This review provides an overview of strategies to identify patients with advanced NAFLD, with an emphasis on the management of associated comorbidities and optimal timing of pre-transplant evaluation. Other topics that have been shown to affect recipient optimization, such as the role of lifestyle changes and bariatric surgery in the management of obesity, as well as sarcopenia in decompensated NASH-related cirrhosis, are addressed.

THU022 - Identification of factors associated with engagement and adherence to a very low calorie diet to achieve significant weight loss in patients with advanced non-alcoholic fatty liver disease: a qualitative evaluation

THU022 - Identification of factors associated with engagement and adherence to a very low calorie diet to achieve significant weight loss in patients with advanced non-alcoholic fatty liver disease: a qualitative evaluation

FRI102 - Efficacy and feasibility of a very low calorie diet to achieve 10% weight loss in patients with advanced non-alcoholic fatty liver disease

FRI102 - Efficacy and feasibility of a very low calorie diet to achieve 10% weight loss in patients with advanced non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease and the risk of metabolic comorbidities: how to manage in clinical practice.

Nonalcoholic fatty liver disease (NAFLD) is a clinical condition that encompasses various forms of liver damage not caused by chronic alcohol consumption. In the absence of other etiologies, it ranges from steatosis to nonalcoholic steatohepatitis and cirrhosis. The prevalence of NAFLD has considerably increased over the last years owing to the current lifestyle (unhealthy diet and sedentarism). Besides, it is associated with metabolic risk factors such as obesity, arterial hypertension, dyslipidemia, and type 2 diabetes. Given the poor prognosis of patients with advanced NAFLD, a practical therapeutic approach is necessary to halt its natural history. However, no licensed drugs have been approved for this purpose to date. Nowadays, we are in a race to find the first drug able to stop the incidence of NAFLD and reverse the disease in patients at more advanced stages. Meanwhile, the management of the NAFLD metabolic overload, including weight loss, cardiovascular protection, insulin sensitization, and lipid reduction, is the only strategy to improve hepatic and extrahepatic outcomes. In this review, we aimed to describe the management of the main metabolic disorders related to NAFLD, such as type 2 diabetes, arterial hypertension, and dyslipidemia.

Intestinal Virome Signature Associated With Severity of Nonalcoholic Fatty Liver Disease

Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD. In a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0-4, 44 patients had an NAS of 5-8 or liver cirrhosis (LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary cholangitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles. Patients with NAFLD and NAS 5-8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0-4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5-8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity. In a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data.

Diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD) Is Independently Associated with Cardiovascular Risk in a Large Austrian Screening Cohort.

Background: Many patients with non-alcoholic fatty liver disease (NAFLD) simultaneously suffer from cardiovascular (CV) disease and often carry multiple CV risk factors. Several CV risk factors are known to drive the progression of fibrosis in patients with NAFLD. Objectives: To investigate whether an established CV risk score, the Framingham risk score (FRS), is associated with the diagnosis of NAFLD and the degree of fibrosis in an Austrian screening cohort for colorectal cancer. Material and Methods: In total, 1965 asymptomatic subjects (59 ± 10 years, 52% females, BMI 27.2 ± 4.9 kg/m2) were included in this study. The diagnosis of NAFLD was present if (1) significantly increased echogenicity in relation to the renal parenchyma was present in ultrasound and (2) viral, autoimmune or hereditary liver disease and excess alcohol consumption were excluded. The FRS (ten-year risk of coronary heart disease) and NAFLD Fibrosis Score (NFS) were calculated for all patients. High CV risk was defined as the highest FRS quartile (>10%). Both univariable and multivariable logistic regression models were used to calculate associations of FRS with NAFLD and NFS. Results: Compared to patients without NAFLD (n = 990), patients with NAFLD (n = 975) were older (60 ± 9 vs. 58 ± 10 years; p < 0.001), had higher BMI (29.6 ± 4.9 vs. 24.9 ± 3.6 kg/m2; p < 0.001) and suffered from metabolic syndrome more frequently (33% vs. 7%; p < 0.001). Cardiovascular risk as assessed by FRS was higher in the NAFLD-group (8.7 ± 6.4 vs. 5.4 ± 5.2%; p < 0.001). A one-percentage-point increase of FRS was independently associated with NAFLD (OR 1.04, 95%CI 1.02–1.07; p < 0.001) after correction for relevant confounders in multivariable logistic regression. In patients with NAFLD, NFS correlated with FRS (r = 0.29; p < 0.001), and FRS was highest in patients with significant fibrosis (F3-4; 11.7 ± 5.4) compared to patients with intermediate results (10.9 ± 6.3) and those in which advanced fibrosis could be ruled-out (F0-2, 7.8 ± 5.9, p < 0.001). A one-point-increase of NFS was an independent predictor of high-risk FRS after correction for sex, age, and concomitant diagnosis of metabolic syndrome (OR 1.30, 95%CI 1.09–1.54; p = 0.003). Conclusion: The presence of NAFLD might independently improve prediction of long-term risk for CV disease and the diagnosis of NAFLD might be a clinically relevant piece in the puzzle of predicting long-term CV outcomes. Due to the significant overlap of advanced NAFLD and high CV risk, aggressive treatment of established CV risk factors could improve prognosis in these patients.