Validation of the new 2021 EASL algorithm for the noninvasive diagnosis of advanced fibrosis in NAFLD.

BACKGROUND AND AIMS: The European Association for the Study of the Liver (EASL) has recently proposed an algorithm for the diagnosis of advanced liver fibrosis. We aimed to evaluate the diagnostic accuracy of this algorithm in nonalcoholic fatty liver disease (NAFLD). APPROACH AND RESULTS: One thousand fifty-one patients with NAFLD, liver biopsy, and four noninvasive tests (NITs; Fibrosis-4 [FIB4], vibration controlled transient elastography [VCTE], FibroMeter, Fibrotest) were included. The enhanced liver fibrosis (ELF) score was available in 396 patients. A cohort of 230 patients from primary care/diabetes clinics had FIB4, VCTE, and ELF. Compared with the performance of single NITs, agreement between two NITs (FIB4 and VCTE, VCTE and patented serum tests) increased specificity and positive predictive value by 20%, thus justifying the sequential use proposed in the EASL algorithm. The FIB4/VCTE/FibroMeter and FIB4/VCTE/Fibrotest algorithms performed similarly, providing 85% diagnostic accuracy and a liver biopsy requirement rate of only 10%. The FIB4/VCTE/ELF algorithm performed similarly in the subgroup where ELF was available. Simulations of algorithm accuracies at different prevalence showed that positive predictive values rapidly increased, reaching a plateau above 75% starting at 15% prevalence. Negative predictive values remained higher than 90% up to 25% prevalence. The rate of liver biopsy requirement remained stable, increasing by only 5% between low and high prevalence settings. When the EASL algorithm was applied in the primary care/diabetes clinic cohort, liver biopsy requirement was only 3%, and the agreement among the three steps provided 75% positive predictive value. CONCLUSIONS: Our study validates the algorithm proposed by the EASL in its latest 2021 guidelines for the diagnosis of advanced fibrosis in the setting of NAFLD.

Serum CC-Chemokine Ligand 2 Is Associated with Visceral Adiposity but Not Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver as a consequence of metabolic perturbations associated with obesity, type 2 diabetes, dyslipidemia, and insulin resistance. People with NAFLD may develop metabolic and cardiovascular complications and/or liver-related complications, especially fibrosis and hepatocellular carcinoma, associated with high morbidity and mortality. Due to the high and increasing prevalence of NAFLD, there is an urgent need to identify people at risk of developing liver fibrosis and complications. CC-chemokine ligand 2 (CCL2) is chemokine that attracts inflammatory monocytes to stressed or injured tissues. Infiltrating inflammatory monocytes and CCL2 are strongly implicated in the pathogenesis of liver disease in animal models; however, evidence in patient cohorts is conflicting. METHODS: We investigated associations between circulating CCL2 and clinical parameters, including fibrosis assessed by liver stiffness measurement, in a cohort of 250 NAFLD patients. We also measured fatty acid binding protein 2 (FABP2), a putative biomarker of intestinal permeability in patients with liver disease, since pro-inflammatory gut-derived microbial products may induce inflammatory chemokines such as CCL2. RESULTS: Serum CCL2 levels were weakly associated with liver stiffness, but the association was no longer significant after accounting for age, diabetes, and BMI in a multivariable model. Consistent with this, girth and BMI were the strongest predictors of elevated circulating CCL2. Serum FABP2 was weakly, but significantly, correlated with CCL2, and negatively correlated with estimated glomerular filtration rate. CONCLUSION: Circulating CCL2 and FABP2 are associated with NAFLD comorbidities but not liver disease progression in patients with NAFLD.

Depressive symptoms in non-alcoholic fatty liver disease are identified by perturbed lipid and lipoprotein metabolism.

Non-alcoholic fatty liver disease (NAFLD) and depression are common disorders and have bidirectional contributing relationships to metabolic syndrome. We aimed to determine whether a fasting serum signature of recent, self-reported depressive symptoms could be identified in a heterogeneous NAFLD cohort using nuclear magnetic resonance (NMR)-based metabolomics integrated with clinical chemistry. Serum nuclear magnetic resonance (NMR) metabolite profiles and corresponding clinical chemistry were compared between patients with depressive symptoms in the last 12-months (n = 81) and patients without recent depressive symptoms (n = 137 controls) using multivariate statistics. Orthogonal partial least squares discriminant analysis (OPLS-DA) of the biochemical and metabolomic data identified NAFLD patients with recent depression with a cross-validated accuracy of 61.5%, independent of age, sex, medication, and other comorbidities. This led to the development of a diagnostic algorithm with AUC 0.83 for future testing in larger clinical cohorts. Serum triglycerides, VLDL cholesterol, and the inflammatory biomarker GlycA were key metabolites increased in patients with recent depressive symptoms, while serum glutamine level was reduced. Here, serum NMR metabolite analysis provides a link between disturbed lipid metabolism, inflammation, and active mental health issues in NAFLD, irrespective of disease severity.

Medication Discrepancies and Regimen Complexity in Decompensated Cirrhosis: Implications for Medication Safety.

Discrepancies between the medicines consumed by patients and those documented in the medical record can affect medication safety. We aimed to characterize medication discrepancies and medication regimen complexity over time in a cohort of outpatients with decompensated cirrhosis, and evaluate the impact of pharmacist-led intervention on discrepancies and patient outcomes. In a randomized-controlled trial (n = 57 intervention and n = 57 usual care participants), medication reconciliation and patient-oriented education delivered over a six-month period was associated with a 45% reduction in the incidence rate of 'high' risk discrepancies (IRR = 0.55, 95%CI = 0.31-0.96) compared to usual care. For each additional 'high' risk discrepancy at baseline, the odds of having ≥ 1 unplanned medication-related admission during a 12-month follow-up period increased by 25% (adj-OR = 1.25, 95%CI = 0.97-1.63) independently of the Child-Pugh score and a history of variceal bleeding. Among participants with complete follow-up, intervention patients were 3-fold less likely to have an unplanned medication-related admission (adj-OR = 0.27, 95%CI = 0.07-0.97) compared to usual care. There was no association between medication discrepancies and mortality. Medication regimen complexity, frequent changes to the regimen and hepatic encephalopathy were associated with discrepancies. Medication reconciliation may improve medication safety by facilitating communication between patients and clinicians about 'current' therapies and identifying potentially inappropriate medicines that may lead to harm.

Serum matrix metalloproteinase 7 (MMP7) is a biomarker of fibrosis in patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the adult population globally. Since liver fibrosis is the most important predictor of liver-related complications in patients with NAFLD, identification of patients with advanced fibrosis among at-risk individuals is an important issue in clinical practice. Transient elastography is the best evaluated non-invasive method used in referral centres to assess liver fibrosis, however serum-based tests, such as the Enhanced Liver Fibrosis (ELF) score, have a practical advantage as first-line tests due to their wider availability and lower cost. We previously identified matrix metalloproteinase 7 (MMP7) as a serum biomarker of histological advanced fibrosis in a mixed-etiology patient cohort. In this study we aimed to determine the association between MMP7 and fibrosis, assessed by transient elastography, in patients with NAFLD. Serum MMP7 levels were measured in a cohort of 228 patients with NAFLD. Associations between MMP7, liver stiffness measurement (LSM), ELF score and clinical parameters were determined using logistic regression modelling. Serum MMP7 was associated with clinically significant fibrosis (LSM ≥ 8.2), independent of age, gender, BMI and diabetes. The addition of MMP7 significantly improved the diagnostic performance of the ELF test, particularly in patients over the age of 60. Combinations of serum biomarkers have the potential to improve the sensitivity and specificity of detection of advanced fibrosis in at-risk patients with NAFLD. We have demonstrated that serum MMP7 is independently associated with clinically significant fibrosis and improves the diagnostic performance of currently available tests in older patients.

Effectiveness of patient-oriented education and medication management intervention in people with decompensated cirrhosis.

People with chronic disease often have poor comprehension of their disease and medications, which can negatively affect health outcomes. In a randomised-controlled trial, we found that patients with decompensated cirrhosis who received a pharmacist-led, patient-oriented education and medication management intervention (n = 57) had greater knowledge of cirrhosis and key self-care tasks compared with usual care (n = 59). Intervention patients also experienced improved quality of life. Dedicated resources are needed to support implementation of evidence-based measures at local centres to improve outcomes.

Decompensated cirrhosis is the commonest presentation for NAFLD patients undergoing liver transplant assessment.

Non-alcoholic fatty liver disease (NAFLD) accounts for 10-15% of orthotopic liver transplants (OLTs) in the UK. Index presentations with cirrhotic decompensation represent missed opportunities for preventive treatment leaving OLT or palliation as the only options.We retrospectively reviewed patient records for all NAFLD patients undergoing assessment for OLT between January 2003 and December 2017.Data were available for 81 patients with NAFLD as the primary diagnosis. Fifty-two patients had decompensated cirrhosis at first presentation; 91.7% presented to secondary care compared to 52.7% referred from primary care (p=0.001). Cirrhosis was not suspected at the time of referral to hospital in 24.7% of patients subsequently assessed for OLT. Most patients undergoing assessment for OLT for NAFLD had decompensated cirrhosis at their first diagnosis of chronic liver disease. These data highlight the plight of patients with NAFLD cirrhosis in whom chronic liver disease is diagnosed late.

Medication-Related Problems in Outpatients With Decompensated Cirrhosis: Opportunities for Harm Prevention.

People with decompensated cirrhosis are often prescribed a complex regimen of therapeutic and prophylactic medications. In other chronic diseases, polypharmacy increases the risk of medication misadventure and medication-related problems (MRPs), with associated increased morbidity, mortality, and health care costs. This study examined MRPs in a cohort of ambulatory patients with a history of decompensated cirrhosis who were enrolled in a randomized controlled trial of a pharmacist-led, patient-oriented medication education intervention and assessed the association between MRPs and patient outcomes. A total of 375 MRPs were identified among 57 intervention patients (median, 6.0; interquartile range, 3.5-8.0 per patient; maximum 17). Nonadherence (31.5%) and indication issues (29.1%) were the most prevalent MRP types. The risk of potential harm associated with MRPs was low in 18.9% of instances, medium in 33.1%, and high in 48.0%, as categorized by a clinician panel using a risk matrix tool. Patients had a greater incidence rate of high-risk MRPs if they had a higher Child-Pugh score (incidence rate ratio [IRR], 1.31; 95% confidence interval [CI], 1.09-1.56); greater comorbidity burden (IRR, 1.15; 95% CI, 1.02-1.29); and were taking more medications (IRR, 1.12; 95% CI, 1.04-1.22). A total of 221 MRPs (58.9%) were resolved following pharmacist intervention. A greater proportion of high-risk MRPs were resolved compared to those of low and medium risk (68.9% versus 49.7%; P < 0.001). During the 12-month follow-up period, intervention patients had a lower incidence rate of unplanned admissions compared to usual care (IRR, 0.52; 95% CI, 0.30-0.92). Conclusion: High-risk MRPs are prevalent among adults with decompensated cirrhosis. Pharmacist intervention facilitated identification and resolution of high-risk MRPs and was associated with reduced incidence rate of unplanned hospital admissions in this group.

Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes.

Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.

Underappreciation of non-alcoholic fatty liver disease by primary care clinicians: limited awareness of surrogate markers of fibrosis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common cause of incidental liver test abnormalities. General practitioners (GP) have a key role in identifying people with NAFLD at risk of significant liver disease. Recent specialist guidelines emphasise the use of fibrosis algorithms or serum biomarkers rather than routine liver tests, to assess advanced fibrosis. AIM: To evaluate primary care clinicians' current approach to diagnosis, management and referral of NAFLD. METHODS: A cross-sectional survey of primary care clinicians was undertaken through a structured questionnaire about NAFLD. A convenience sample of general practice clinics and general practice conferences in Metropolitan Brisbane and regional south east Queensland was selected. RESULTS: A total of 108 primary care clinicians completed the survey (participation rate 100%). Fifty-one percent of respondents considered the prevalence of NAFLD in the general population to be ≤10%. Twenty-four percent of respondents felt that liver enzymes were sufficiently sensitive to detect underlying NAFLD. Most respondents were unsure whether the Fibrosis 4 score (62.7% unsure) or Enhanced Liver Fibrosis score (63.7% unsure) could help to identify advanced fibrosis or cirrhosis. Although 47% of respondents said they would refer a patient to a Gastroenterologist/Hepatologist if they suspect the patient has NAFLD, 44.1% do not make any referrals. Of concern, 70.6% of clinicians said they were unlikely to refer a patient to Hepatology unless liver function tests are abnormal. CONCLUSION: Our findings demonstrate that many primary care clinicians underestimate the prevalence of NAFLD and under-recognise the clinical spectrum of NAFLD and how this is assessed.

Alcohol Consumption in Diabetic Patients with Nonalcoholic Fatty Liver Disease.

AIM: To examine the association between lifetime alcohol consumption and significant liver disease in type 2 diabetic patients with NAFLD. METHODS: A cross-sectional study assessing 151 patients with NAFLD at risk of clinically significant liver disease. NAFLD fibrosis severity was classified by transient elastography; liver stiffness measurements ≥8.2 kPa defined significant fibrosis. Lifetime drinking history classified patients into nondrinkers, light drinkers (always ≤20 g/day), and moderate drinkers (any period with intake >20 g/day). RESULT: Compared with lifetime nondrinkers, light and moderate drinkers were more likely to be male (p = 0.008) and to be Caucasian (p = 0.007) and to have a history of cigarette smoking (p = 0.000), obstructive sleep apnea (p = 0.003), and self-reported depression (p = 0.003). Moderate drinkers required ≥3 hypoglycemic agents to maintain diabetic control (p = 0.041) and fibrate medication to lower blood triglyceride levels (p = 0.044). Compared to lifetime nondrinkers, light drinkers had 1.79 (95% CI: 0.67-4.82; p = 0.247) and moderate drinkers had 0.91 (95% CI: 0.27-3.10; p = 0.881) times the odds of having liver stiffness measurements ≥8.2 kPa (adjusted for age, gender, and body mass index). CONCLUSIONS: In diabetic patients with NAFLD, light or moderate lifetime alcohol consumption was not significantly associated with liver fibrosis. The impact of lifetime alcohol intake on fibrosis progression and diabetic comorbidities, in particular obstructive sleep apnea and hypertriglyceridemia, requires further investigation.

Medication beliefs predict medication adherence in ambulatory patients with decompensated cirrhosis.

AIM: To investigate the impact of medication beliefs, illness perceptions and quality of life on medication adherence in people with decompensated cirrhosis. METHODS: One hundred adults with decompensated cirrhosis completed a structured questionnaire when they attended for routine outpatient hepatology review. Measures of self-reported medication adherence (Morisky Medication Adherence Scale), beliefs surrounding medications (Beliefs about Medicines Questionnaire), perceptions of illness and medicines (Brief Illness Perception Questionnaire), and quality of life (Chronic Liver Disease Questionnaire) were examined. Clinical data were obtained via patient history and review of medical records. Least absolute shrinkage and selection operator and stepwise backwards regression techniques were used to construct the multivariable logistic regression model. Statistical significance was set at alpha = 0.05. RESULTS: Medication adherence was "High" in 42% of participants, "Medium" in 37%, and "Low" in 21%. Compared to patients with "High" adherence, those with "Medium" or "Low" adherence were more likely to report difficulty affording their medications (P < 0.001), lower perception of treatment helpfulness (P = 0.003) and stronger medication concerns relative to medication necessity beliefs (P = 0.003). People with "Low" adherence also experienced greater symptom burden and poorer quality of life, including more frequent abdominal pain (P = 0.023), shortness of breath (P = 0.030), and emotional disturbances (P = 0.050). Multivariable analysis identified having stronger medication concerns relative to necessity beliefs (Necessity-Concerns Differential ≤ 5, OR = 3.66, 95%CI: 1.18-11.40) and more frequent shortness of breath (shortness of breath score ≤ 3, OR = 3.87, 95%CI: 1.22-12.25) as independent predictors of "Low"adherence. CONCLUSION: The association between "Low" adherence and patients having strong concerns or doubting the necessity or helpfulness of their medications should be explored further given the clinical relevance.

Patient-oriented education and medication management intervention for people with decompensated cirrhosis: study protocol for a randomized controlled trial.

BACKGROUND: People with decompensated cirrhosis require complex medical care and are often prescribed an intricate and frequently changing medication and lifestyle regimen. However, many patients mismanage their medications or have poor comprehension of their disease and self-management tasks. This can lead to harm, hospitalization, and death. METHODS/DESIGN: A patient-oriented education and medication management intervention has been developed for implementation at a tertiary hospital hepatology outpatient center in Queensland, Australia. Consenting patients with decompensated cirrhosis will be randomly allocated to education intervention or usual care treatment arms when they attend routine follow-up appointments. In the usual care arm, participants will be reviewed by their hepatologist according to the current model of care in the hepatology clinic. In the intervention arm, participants will be reviewed by a clinical pharmacist to receive the education and medication management intervention at baseline in addition to review by their hepatologist. Intervention participants will also receive three further educational contacts from the clinical pharmacist within the following 6-month period, in addition to routine hepatologist review that is scheduled within this time frame. All participants will be surveyed at baseline and follow-up (approximately 6 months post-enrollment). Validated questionnaire tools will be used to determine participant adherence, medication beliefs, illness perceptions, and quality of life. Patients' knowledge of dietary and lifestyle modifications, their current medications, and other clinical data will be obtained from the survey, patient interview, and medical records. Patient outcome data will be collected at 52 weeks. DISCUSSION: The intervention described within this protocol is ready to adapt and implement in hepatology ambulatory care centers globally. Investigation of potentially modifiable variables that may impact medication management, in addition to the effect of a clinical pharmacist-driven education and medication management intervention on modifying these variables, will provide valuable information for future management of these patients. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry identifier: ACTRN12616000780459 . Registered on 15 June 2016.

Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation.

BACKGROUND AND AIMS: Liver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence. METHODS: Peripheral blood monocyte surface marker (CD14, CD16, CD163, CSF1R, CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, HLA-DR, CD62L, SIGLEC-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated TNF production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) (classified as non-advanced disease, compensated cirrhosis and decompensated cirrhosis) and healthy controls (n = 11) by flow cytometry. RESULTS: The selected markers exhibited similar monocyte-subset-specific expression patterns between patients and controls. Monocyte phenotypic signatures differed between NAFLD and HCV patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV. In both cohorts, monocyte CCR2 expression was reduced and CCR4 elevated over controls. CD62L expression was specifically elevated in patients with decompensated cirrhosis and positively correlated with the model-for-end-stage-liver-disease score. Functionally, monocytes from patients with decompensated cirrhosis had equal phagocytic capacity, but displayed features of dysfunction, characterised by lower HLA-DR expression and blunted oxidative responses. Lower monocyte TNF production in response to LPS stimulation correlated with time to death in 7 (46%) of the decompensated patients who died within 8 months of recruitment. CONCLUSIONS: Chronic HCV and NAFLD differentially affect circulating monocyte phenotype, suggesting specific injury-induced signals may contribute to hepatic monocyte recruitment and systemic activation state. Monocyte function, however, was similarly impaired in patients with both HCV and NAFLD, particularly in advanced disease, which likely contributes to the increased susceptibility to infection in these patients.

Relationship between contact force sensing technology and medium-term outcome of atrial fibrillation ablation: a multicenter study of 600 patients.

INTRODUCTION: Contact force sensing (CFS) technology improves acute pulmonary vein isolation durability; however, its impact on the clinical outcome of ablating atrial fibrillation (AF) is unknown. METHODS AND RESULTS: First time AF ablation procedures employing CFS from 4 centers were matched retrospectively to those without CFS in a 1:2 manner by type of AF. Freedom from atrial tachyarrhythmia was defined as the primary outcome measure, and fluoroscopy time the secondary outcome measure. Nineteen possible explanatory variables were tested in addition to CFS. A total of 600 AF ablation procedures (200 using CFS and 400 using non-CFS catheters) performed between 2010 and 2012 (46% paroxysmal, 36% persistent, 18% long-lasting persistent) were analyzed. The mean follow-up duration was 11.4 ± 4.7 months-paroxysmal AF 11.2 ± 4.1 CFS versus 11.3 ± 3.9 non-CFS (P = 0.745)-nonparoxysmal AF 10.4 ± 4.5 CFS versus 11.9 ± 5.4 non-CFS (P = 0.015). The use of a CFS catheter independently predicted clinical success in ablating paroxysmal AF (HR 2.24 [95% CIs 1.29-3.90]; P = 0.004), but not nonparoxysmal AF (HR 0.73 [0.41-1.30]; P = 0.289) in a multivariate analysis that included follow-up duration. Among all cases, the use of CFS catheters was associated with reduced fluoroscopy time in multivariate analysis (reduction by 7.7 [5.0-10.5] minutes; P < 0.001). Complication rates were similar in both groups. CONCLUSIONS: At medium-term follow-up, CFS catheter technology is associated with significantly improved outcome of first time catheter ablation of paroxysmal AF, but not nonparoxysmal AF. Fluoroscopy time was lower when CFS technology was employed in all types of AF ablation procedures.