MAFLD in adults: non-invasive tests for diagnosis and monitoring of MAFLD.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the liver manifestation of a metabolic syndrome and is highly prevalent in the general population. There has been significant progress in non-invasive tests for MAFLD, from the diagnosis of fatty liver and monitoring of liver fat content in response to intervention, to evaluation of liver fibrosis and its change over time, and from risk stratification of patients within the context of clinical care pathways, to prognostication. Various non-invasive tests have also been developed to assess for fibrotic metabolic dysfunction-associated steatohepatitis, which has emerged as an important diagnostic goal, particularly in the context of clinical trials. Non-invasive tests can be used to diagnose clinically significant portal hypertension so that intervention can be administered to reduce the risk of decompensation. Furthermore, the use of risk stratification algorithms can identify at-risk patients for hepatocellular carcinoma surveillance. Beyond the liver, various tests that evaluate cardiovascular disease risk, assess sarcopenia and measure patient reported outcomes, can be utilized to improve the care of patients with MAFLD. This review provides an up-to-date overview of these non-invasive tests and the limitations of liver biopsy in the management of patients with MAFLD.

A randomized multicenter trial of a chronic disease management intervention for decompensated cirrhosis. The Australian Liver Failure (ALFIE) trial.

BACKGROUND AND AIMS: Improving the care of decompensated cirrhosis is a significant clinical challenge. The primary aim of this trial was to assess the efficacy of a chronic disease management (CDM) model to reduce liver-related emergency admissions (LREA). The secondary aims were to assess model effects on quality-of-care and patient-reported outcomes. APPROACH AND RESULTS: The study design was a 2-year, multicenter, randomized controlled study with 1:1 allocation of a CDM model versus usual care. The study setting involved both tertiary and community care. Participants were randomly allocated following a decompensated cirrhosis admission. The intervention was a multifaceted CDM model coordinated by a liver nurse. A total of 147 participants (intervention=75, control=71) were recruited with a median Model for End-Stage Liver Disease score of 19. For the primary outcome, there was no difference in the overall LREA rate for the intervention group versus the control group (incident rate ratio 0.89; 95% CI: 0.53-1.50, p=0.666) or in actuarial survival (HR=1.14; 95% CI: 0.66-1.96, p=0.646). However, there was a reduced risk of LREA due to encephalopathy in the intervention versus control group (HR=1.87; 95% CI: 1.18-2.96, p=0.007). Significant improvement in quality-of-care measures was seen for the performance of bone density (p<0.001), vitamin D testing (p<0.001), and HCC surveillance adherence (p=0.050). For assessable participants (44/74 intervention, 32/71 controls) significant improvements in patient-reported outcomes at 3 months were seen in self-management ability and quality of life as assessed by visual analog scale (p=0.044). CONCLUSIONS: This CDM intervention did not reduce overall LREA events and may not be effective in decompensated cirrhosis for this end point.

Adiposity associates with lower plasma resolvin E1 (Rve1): a population study.

BACKGROUND: Inadequate inflammation resolution may contribute to persistent low-grade inflammation that accompanies many chronic conditions. Resolution of inflammation is an active process driven by Specialized Pro-resolving Mediators (SPM) that derive from long chain n-3 and n-6 fatty acids. This study examined plasma SPM in relation to sex differences, lifestyle and a broad range cardiovascular disease (CVD) risk factors in 978, 27-year olds from the Australian Raine Study. METHODS: Plasma SPM pathway intermediates (18-HEPE, 17-HDHA and 14-HDHA), and SPM (E- and D-series resolvins, PD1, MaR1) and LTB4 were measured by liquid chromatography-tandem mass spectrometry (LCMSMS). Pearson correlations and multiple regression analyses assessed relationships between SPM and CVD risk factors. Unpaired t-tests or ANOVA assessed the effect of sex, smoking, unhealthy alcohol consumption and obesity on SPM. RESULTS: Women had higher 17-HDHA (p = 0.01) and lower RvE1 (p < 0.0001) and RvD1 (p = 0.05) levels compared with men. In univariate analysis, obesity associated with lower RvE1 (p = 0.002), whereas smoking (p < 0.001) and higher alcohol consumption (p < 0.001) associated with increased RvE1. In multiple regression analysis, plasma RvE1 was negatively associated with a range of measures of adiposity including BMI, waist circumference, waist-to-height ratio, abdominal subcutaneous fat volume, and skinfold thicknesses in both men and women. CONCLUSION: This population study suggests that a deficiency in plasma RvE1 may occur in response to increasing adiposity. This observation could be relevant to ongoing inflammation that associates with CVD and other chronic diseases.

The future of International Classification of Diseases coding in steatotic liver disease: An expert panel Delphi consensus statement.

BACKGROUND: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. METHODS: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. RESULTS: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). CONCLUSIONS: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

Successful Liver Retransplantation in a Patient With Disseminated Aspergillosis and Nocardiosis: A Case Report.

BACKGROUND: Clinical guidelines list active fungal infection and sepsis as contraindications to liver transplantation due to the risk of worsening infection with immunosuppression postoperatively. Mortality from systemic opportunistic infections in transplant recipients is high, approaching 100% for disseminated aspergillosis. However, the optimal duration of treatment required before transplant is unclear. Additionally, delaying surgery while the infection is treated risks death from hepatic decompensation and physical deconditioning, preventing progression to transplantation. CASE REPORT: Here, we present a patient who underwent successful repeat liver transplantation for recurrent autoimmune hepatitis and graft rejection while undergoing treatment for disseminated aspergillosis and nocardiosis. He had pulmonary, hepatic, and central nervous system involvement. He had received 2 months of antimicrobials but had ongoing radiologic evidence of infection when listed for retransplantation. He remains well and infection-free 1 year postoperatively. CONCLUSION: Few cases of successful liver transplantation in the setting of disseminated aspergillosis have been reported previously. To our knowledge, this is the first successful liver transplant in a patient with disseminated nocardial infection.

Higher Overall Intakes Are the Defining Feature of Dietary Intakes in NAFLD and Compared to the General Population.

We aimed to compare the dietary intakes of Australian patients with non-alcoholic fatty liver disease (NAFLD) to general Australian population intake data and determine whether the intake of any nutrient or food group was able to predict the degree of steatosis. Dietary data from fifty adult patients with NAFLD were compared to intake data from the Australian Health Survey for energy, macronutrients, fat sub-types, alcohol, iron, folate, sugar, fibre, sodium and caffeine. Linear regression models adjusting for potential confounders (age, sex, physical activity and body mass index) were used to examine predictive relationships between hepatic steatosis (quantified via magnetic resonance spectroscopy) and dietary components. The mean percentage differences between NAFLD and Australian usual intakes were significant for energy, protein, total fat, saturated fat, monounsaturated and polyunsaturated fats (all p < 0.001). The contribution of fat and protein to total energy intake was significantly higher in the NAFLD cohort (p < 0.05). No individual nutrients or food groups were strongly related to hepatic fat in the adjusted models. Higher overall consumption appears to be a major feature of dietary intake in NAFLD when compared to the general population. A whole-diet approach to NAFLD treatment and prevention is likely to be more effective than focusing on single food components.

Liver fibrosis quantified by image morphometry predicts clinical outcomes in patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Liver fibrosis predicts adverse clinical outcomes, such as liver-related death (LRD) and hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the accuracy of semi-automated quantification of collagen proportionate area (CPA) as an objective new method for predicting clinical outcomes. METHOD: Liver biopsies from patients with NAFLD underwent computerized image morphometry of Sirius Red staining with CPA quantification performed by ImageScope. Clinical outcomes, including total mortality, LRD, and combined liver outcomes (liver decompensation, HCC, or LRD), were determined by medical records and population-based data-linkage. The accuracy of CPA for predicting outcomes was compared with non-invasive fibrosis tests (Hepascore, FIB-4, APRI). RESULTS: A total of 295 patients (mean age 50 years) were followed for a median (range) of 9 (0.2-25) years totalling 3253 person-years. Patients with CPA ≥ 10% had significantly higher risks for total death [hazard ratio (HR): 5.0 (1.9-13.2)], LRD [19.0 (2.0-182.0)], and combined liver outcomes [15.6 (3.1-78.6)]. CPA and pathologist fibrosis staging (FS) showed similar accuracy (AUROC) for the prediction of total death (0.68 vs. 0.70), LRD (0.72 vs. 0.77) and combined liver outcomes (0.75 vs. 0.78). Non-invasive serum markers Hepascore, APRI, and FIB-4 reached higher AUROC; however, they were not statistically significant compared to that of CPA except for Hepascore in predicting total mortality (0.86 vs. 0.68, p = 0.009). CONCLUSION: Liver fibrosis quantified by CPA analysis was significantly associated with clinical outcomes including total mortality, LRD, and HCC. CPA achieved similar accuracy in predicting outcomes compared to pathologist fibrosis staging and non-invasive serum markers.

Validation of the Blood Test MACK-3 for the Noninvasive Diagnosis of Fibrotic Nonalcoholic Steatohepatitis: An International Study With 1924 Patients.

BACKGROUND & AIMS: Drug development in nonalcoholic steatohepatitis (NASH) is hampered by a high screening failure rate that reaches 60% to 80% in therapeutic trials, mainly because of the absence of fibrotic NASH on baseline liver histology. MACK-3, a blood test including 3 biomarkers (aspartate aminotransferase, homeostasis model assessment, and cytokeratin 18), recently was developed for the noninvasive diagnosis of fibrotic NASH. We aimed to validate the diagnostic accuracy of this noninvasive test in an international multicenter study. METHODS: A total of 1924 patients with biopsy-proven nonalcoholic fatty liver disease from 10 centers in Asia, Australia, and Europe were included. The blood test MACK-3 was calculated for all patients. FibroScan-aspartate aminotransferase score (FAST), an elastography-based test for fibrotic NASH, also was available in a subset of 655 patients. Fibrotic NASH was defined as the presence of NASH on liver biopsy with a Nonalcoholic Fatty Liver Disease Activity Score of 4 or higher and fibrosis stage of F2 or higher according to the NASH Clinical Research Network scoring system. RESULTS: The area under the receiver operating characteristic of MACK-3 for fibrotic NASH was 0.791 (95% CI 0.768-0.814). Sensitivity at the previously published MACK-3 threshold of less than 0.135 was 91% and specificity at a greater than 0.549 threshold was 85%. The MACK-3 area under the receiver operating characteristic was not affected by age, sex, diabetes, or body mass index. MACK-3 and FAST results were well correlated (Spearman correlation coefficient, 0.781; P < .001). Except for an 8% higher rate of patients included in the grey zone, MACK-3 provided similar accuracy to that of FAST. Both tests included 27% of patients in their rule-in zone, with 85% specificity and 35% false positives (screen failure rate). CONCLUSIONS: The blood test MACK-3 is an accurate tool to improve patient selection in NASH therapeutic trials.

Comparative Accuracy of Clinical Fibrosis Markers, Hepascore and Fibroscan® to Detect Advanced Fibrosis in Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND: Non-invasive tests are widely used to diagnose fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), however, the optimal method remains unclear. We compared the accuracy of simple serum models, a serum model incorporating direct measures of fibrogenesis (Hepascore), and Fibroscan®, for detecting fibrosis in NAFLD. METHODS: NAFLD patients undergoing liver biopsy were evaluated with Hepascore, NAFLD Fibrosis Score (NFS), FIB-4 and AST-platelet ratio index (APRI), with a subset (n = 131) undergoing Fibroscan®. Fibrosis on liver biopsy was categorized as advanced (F3-4) or cirrhosis (F4). Accuracy was determined by area under receiving operating characteristic curves (AUC). Indeterminate ranges were calculated using published cut-offs. RESULTS: In 271 NAFLD patients, 83 (31%) had F3-4 and 47 (17%) cirrhosis. 6/131 (4%) had an unreliable Fibroscan®. For the detection of advanced fibrosis, the accuracy of Hepascore (AUC 0.88) was higher than FIB-4 (0.73), NFS (0.72) and APRI (0.69) (p < 0.001 for all). Hepascore had similar accuracy to Fibroscan® (0.80) overall, but higher accuracy in obese individuals (0.91 vs 0.80, p = 0.001). Hepascore more accurately identified patients with cirrhosis than APRI (AUC 0.85 vs 0.71, p = 0.01) and NFS (AUC 0.73, p = 0.01) but performed similar to FIB-4 and Fibroscan®. For the determination of F3-4, the proportion of patients in indeterminate area was lower for Hepascore (4.8%), compared to FIB-4 (42%), NFS (36%) and APRI (44%) (p < 0.001 for all). CONCLUSIONS: Hepascore has greater accuracy and a lower indeterminate range than simple serum fibrosis tests for advanced fibrosis in NAFLD, and greater accuracy than Fibroscan® in obese individuals.

Predicting liver-related events in NAFLD: A predictive model.

BACKGROUND AND AIMS: Management of NAFLD involves noninvasive prediction of fibrosis, which is a surrogate for patient outcomes. We aimed to develop and validate a model predictive of liver-related events (LREs) of decompensation and/or HCC and compare its accuracy with fibrosis models. APPROACH AND RESULTS: Patients with NAFLD from Australia and Spain who were followed for up to 28 years formed derivation (n = 584) and validation (n = 477) cohorts. Competing risk regression and information criteria were used for model development. Accuracy was compared with fibrosis models using time-dependent AUC analysis. During follow-up, LREs occurred in 52 (9%) and 11 (2.3%) patients in derivation and validation cohorts, respectively. Age, type 2 diabetes, albumin, bilirubin, platelet count, and international normalized ratio were independent predictors of LRE and were combined into a model [NAFLD outcomes score (NOS)]. The NOS model calibrated well [calibration slope, 0.99 (derivation), 0.98 (validation)] with excellent overall performance [integrated Brier score, 0.07 (derivation) and 0.01 (validation)]. A cutoff ≥1.3 identified subjects at a higher risk of LRE, (sub-HR 24.6, p < 0.001, 5-year cumulative incidence 38% vs 1.0%, respectively). The predictive accuracy at 5 and 10 years was excellent in both derivation (time-dependent AUC,0.92 and 0.90, respectively) and validation cohorts (time-dependent AUC,0.80 and 0.82, respectively). The NOS was more accurate than the fibrosis-4 or NAFLD fibrosis score for predicting LREs at 5 and 10 years ( p < 0.001). CONCLUSIONS: The NOS model consists of readily available measures and has greater accuracy in predicting outcomes in patients with NAFLD than existing fibrosis models.

Consensus Statement on the definition and classification of metabolic hyperferritinaemia.

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.

Cardiovascular disease in metabolic-associated fatty liver disease.

PURPOSE OF REVIEW: Fatty liver disease is increasingly common worldwide and is associated with an increased risk of cardiovascular disease (CVD). RECENT FINDINGS: This review describes the cardiovascular outcomes, clinical assessment and management as well as the impact of emerging drug treatment on CVD risk. SUMMARY: Patients with fatty liver require CVD risk assessment including consideration of statin therapy. Emerging therapeutic drugs for fatty liver may have both adverse and beneficial effects on CVD risk.

Real-world evidence on non-invasive tests and associated cut-offs used to assess fibrosis in routine clinical practice.

Background & Aims: Non-invasive tests (NITs) offer a practical solution for advanced fibrosis identification in non-alcoholic fatty liver disease (NAFLD). Despite increasing implementation, their use is not standardised, which can lead to inconsistent interpretation and risk stratification. We aimed to assess the types of NITs and the corresponding cut-offs used in a range of healthcare settings. Methods: A survey was distributed to a convenience sample of liver health experts who participated in a global NAFLD consensus statement. Respondents provided information on the NITs used in their clinic with the corresponding cut-offs and those used in established care pathways in their areas. Results: There were 35 respondents from 24 countries, 89% of whom practised in tertiary level settings. A total of 14 different NITs were used, and each respondent reported using at least one (median = 3). Of the respondents, 80% reported using FIB-4 and liver stiffness by vibration-controlled transient elastography (Fibroscan®), followed by the NAFLD fibrosis score (49%). For FIB-4, 71% of respondents used a low cut-off of <1.3 (range <1.0 to <1.45) and 21% reported using age-specific cut-offs. For Fibroscan®, 21% of respondents used a single liver stiffness cut-off: 8 kPa in 50%, while the rest used 7.2 kPa, 7.8 kPa and 8.7 kPa. Among the 63% of respondents who used lower and upper liver stiffness cut-offs, there were variations in both values (<5 to <10 kPa and >7.5 to >20 kPa, respectively). Conclusions: The cut-offs used for the same NITs for NAFLD risk stratification vary between clinicians. As cut-offs impact test performance, these findings underscore the heterogeneity in risk-assessment and support the importance of establishing consistent guidelines on the standardised use of NITs in NAFLD management. Lay summary: Owing to the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population it is important to identify those who have more advanced stages of liver fibrosis, so that they can be properly treated. Non-invasive tests (NITs) provide a practical way to assess fibrosis risk in patients. However, we found that the cut-offs used for the same NITs vary between clinicians. As cut-offs impact test performance, these findings highlight the importance of establishing consistent guidelines on the standardised use of NITs to optimise clinical management of NAFLD.

Geographical similarity and differences in the burden and genetic predisposition of NAFLD.

NAFLD has become a major public health problem for more than 2 decades with a growing prevalence in parallel with the epidemic of obesity and type 2 diabetes (T2D). The disease burden of NAFLD differs across geographical regions and ethnicities. Variations in prevalence of metabolic diseases, extent of urban-rural divide, dietary habits, lifestyles, and the prevalence of NAFLD risk and protective alleles can contribute to such differences. The rise in NAFLD has led to a remarkable increase in the number of cases of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver-related mortality related to NAFLD. Moreover, NAFLD is associated with multiple extrahepatic manifestations. Most of them are risk factors for the progression of liver fibrosis and thus worsen the prognosis of NAFLD. All these comorbidities and complications affect the quality of life in subjects with NAFLD. Given the huge and growing size of the population with NAFLD, it is expected that patients, healthcare systems, and the economy will suffer from the ongoing burden related to NAFLD. In this review, we examine the disease burden of NAFLD across geographical areas and ethnicities, together with the distribution of some well-known genetic variants for NAFLD. We also describe some special populations including patients with T2D, lean patients, the pediatric population, and patients with concomitant liver diseases. We discuss extrahepatic outcomes, patient-reported outcomes, and economic burden related to NAFLD.

A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.

The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.