Implementing non-invasive markers for liver fibrosis in clinical practice

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Accelerated CCl4-Induced Liver Fibrosis in Hjv-/- Mice, Associated with an Oxidative Burst and Precocious Profibrogenic Gene Expression

Hereditary hemochromatosis is commonly associated with liver fibrosis. Likewise, hepatic iron overload secondary to chronic liver diseases aggravates liver injury. To uncover underlying molecular mechanisms, hemochromatotic hemojuvelin knockout (Hjv-/-) mice and wild type (wt) controls were intoxicated with CCl4. Hjv-/- mice developed earlier (by 2-4 weeks) and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I)-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF and, notably, the iron-regulatory hormone hepcidin. Hence, CCl4-induced liver fibrogenesis was exacerbated and progressed precociously in Hjv−/− animals. Even though livers of naïve Hjv−/− mice were devoid of apparent pathology, they exhibited oxidative stress and immunoreactivity towards α-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2–3 fold vs. wt, p<0.05) levels of α1-(I)-collagen, TGF-β1, endothelin-1 and PDGF mRNAs, indicative of early fibrogenesis. Our data suggest that hepatic iron overload in parenchymal cells promotes oxidative stress and triggers premature profibrogenic gene expression, contributing to accelerated onset and precipitous progression of liver fibrogenesis

Utilization and long‐term persistence of direct oral anticoagulants among patients with nonvalvular atrial fibrillation and liver disease

Aims: We characterized the utilization and long-term treatment persistence of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF) and liver disease. Method: Using the UK Clinical Practice Research Datalink, we assembled a population-based cohort of NVAF patients with liver disease initiating oral anticoagulants between 2011 and 2020. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) of the association between patient characteristics and initiation of DOACs vs vitamin K antagonists (VKAs). Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs of the association between patient characteristics and the switch from VKAs to DOACs vs remaining on VKAs. We also assessed the 5-year treatment persistence with DOACs vs VKAs, and whether ischemic stroke or bleeding preceded treatment discontinuation. Results: Our cohort included 3167 NVAF patients with liver disease initiating DOACs (n = 2247, 71%) or VKAs (n = 920, 29%). Initiators of DOACs were more likely to have prior ischemic stroke (OR 1.44, 95% CI 1.12-1.85) than VKA initiators but less likely to have used antiplatelet agents (OR 0.66, 95% CI 0.53-0.82). Patients switching to DOACs were more likely to have used selective serotonin reuptake inhibitors (HR 1.64, 95% CI 1.13-2.37) than those remaining on VKAs. At 5 years, 31% of DOAC initiators and 9% of VKA initiators remained persistent. Only few patients were diagnosed with ischemic stroke or bleeding prior to treatment discontinuation. Conclusion: Most NVAF patients with liver disease initiated treatment with DOACs. Long-term persistence with DOACs was higher than with VKAs but remained relatively low

Accuracy, Reliability, and Comprehensiveness of ChatGPT-Generated Medical Responses for Patients With Nonalcoholic Fatty Liver Disease

: Nonalcoholic fatty liver disease (NAFLD) is an increasing global health problem and is expected to become the leading indication for liver transplantation.1 There are no approved NAFLD-specific pharmacotherapies, and lifestyle modification is the primary recommended therapy.2 Innovative approaches to facilitate the implementation and long-term maintenance of lifestyle changes are needed to address the challenging and complex nature of the management of NAFLD, which recently was renamed as metabolic dysfunction-associated steatotic liver disease, to overcome the limitations and stigma of the previous name.3,4 Artificial intelligence (AI)-powered chatbots have been shown to provide effective personalized support and education to patients, with the potential to complement health care resources. The OpenAI Foundation's AI chatbot, Chat Generative Pretrained Transformer (ChatGPT), has attracted worldwide attention for its remarkable performance in question-answer tasks.5-7 This study evaluated the accuracy, completeness, and comprehensiveness of chatGPT's responses to NAFLD-related questions, with the aim of assessing its performance in addressing patients' queries about the disease and lifestyle behaviors

Angiotensin I-converting enzyme type 2 expression is increased in pancreatic islets of type 2 diabetic donors

Aims: Angiotensin I-converting enzyme type 2 (ACE2), a pivotal SARS-CoV-2 receptor, has been shown to be expressed in multiple cells, including human pancreatic beta-cells. A putative bidirectional relationship between SARS-CoV-2 infection and diabetes has been suggested, confirming the hypothesis that viral infection in beta-cells may lead to new-onset diabetes or worse glycometabolic control in diabetic patients. However, whether ACE2 expression levels are altered in beta-cells of diabetic patients has not yet been investigated. Here, we aimed to elucidate the in situ expression pattern of ACE2 in Type 2 diabetes (T2D) with respect to non-diabetic donors which may account for a higher susceptibility to SARS-CoV-2 infection in beta-cells.Material and Methods: Angiotensin I-converting enzyme type 2 immunofluorescence analysis using two antibodies alongside insulin staining was performed on formalin-fixed paraffin embedded pancreatic sections obtained from n = 20 T2D and n = 20 non-diabetic (ND) multiorgan donors. Intensity and colocalisation analyses were performed on a total of 1082 pancreatic islets. Macrophage detection was performed using anti-CD68 immunohistochemistry on serial sections from the same donors.Results: Using two different antibodies, ACE2 expression was confirmed in beta-cells and in pancreas microvasculature. Angiotensin I-converting enzyme type 2 expression was increased in pancreatic islets of T2D donors in comparison to ND controls alongside with a higher colocalisation rate between ACE2 and insulin using both anti-ACE2 antibodies. CD68(+) cells tended to be increased in T2D pancreata, in line with higher ACE2 expression observed in serial sections.Conclusions: Higher ACE2 expression in T2D islets might increase their susceptibility to SARS-CoV-2 infection during COVID-19 in T2D patients, thus worsening glycometabolic outcomes and disease severity

The Relationship between Visceral Adiposity and Nonalcoholic Fatty Liver Disease Diagnosed by Controlled Attenuation Parameter in People with HIV: A Pilot Study

Background: Fat alterations are frequent in people with HIV (PWH) and predict worse cardiometabolic outcomes. Visceral adipose tissue (VAT) is associated with ectopic fat accumulation in the liver. We aimed to investigate nonalcoholic fatty liver disease (NAFLD) diagnosed by controlled attenuation parameter (CAP) as a potential marker of visceral adiposity in PWH. Methods: We conducted a prospective pilot study of HIV mono-infected patients undergoing metabolic characterization and paired CAP measured by transient elastography with dual-energy X-ray absorptiometry (DEXA) scan. NAFLD was defined as CAP &gt;= 285 dB/m, in absence of alcohol abuse. Excess visceral adiposity was defined as VAT &gt; 1.32 Kg. Pairwise correlation, area under the curve (AUC) and logistic regression analysis were employed to study the association between VAT and CAP. Results: Thirty patients were included, of whom 50% had NAFLD. CAP was correlated with VAT (r = 0.650, p &lt; 0.001) measured by DEXA scan. After adjusting for duration of HIV infection, body mass index and waist circumference, CAP remained the only independent predictor of excess VAT (adjusted odds ratio 1.05, 95% confidence interval [CI] 1.01-1.10). The AUC analysis determined CAP had excellent performance to diagnose excess VAT (AUC 0.92, 95% CI 0.81-1.00), higher than BMI and waist circumference. The optimized CAP cut-off to diagnose excess VAT was 266 dB/m, with a sensitivity of 88.3% and a specificity of 84.6%. Conclusions: NAFLD diagnosed by CAP is associated with VAT in PWH independently of anthropometric measures of obesity. CAP may be a potential diagnostic marker of visceral adiposity in the practice of HIV medicine

Hepatic steatosis progresses faster in HIV mono-infected than HIV/HCV co-infected patients and is associated with liver fibrosis

Background & Aims Hepatic steatosis (HS) seems common in patients infected with human immunodeficiency virus (HIV). However, the relative effect of HIV, as well as hepatitis C virus (HCV) in those co-infected, and the influence of HS on liver fibrosis progression are unclear. Methods The LIVEr disease in HIV (LIVEHIV) is a Canadian prospective Cohort using transient elastography and associated controlled attenuation parameter (CAP) to screen for HS and liver fibrosis in unselected HIV-infected adults. HS progression was defined as development of any grade HS (CAP ≥248 dB/m), or transition to severe HS (CAP ≥292 dB/m) for those with any grade HS at baseline. Fibrosis progression was defined as development of significant liver fibrosis (liver stiffness measurement [LSM] ≥7.1kPa), or transition to cirrhosis (LSM ≥12.5kPa) for those with significant liver fibrosis at baseline. Cox regression analysis was used to assess predictors of HS and fibrosis progression. Results A prospective cohort study was conducted, which included 726 HIV-infected patients (22.7% HCV co-infected). Prevalence of any grade HS did not differ between HIV mono-infected and HIV/HCV co-infected patients (36.1% vs 38.6%, respectively). 313 patients were followed for a median of 15.4 (interquartile range 8.5-23.0) months. The rate of HS progression was 37.8 (95% confidence interval [CI] 29.2-49.0) and 21.9 (95% CI 15.6-30.7) per 100 person-years in HIV mono-infection and HIV/HCV co-infection, respectively. HCV co-infection was an independent negative predictor of HS progression (adjusted hazard ratio [aHR] 0.50, 95% CI 0.28-0.89). HS predicted liver fibrosis progression in HIV mono-infection (aHR 4.18, 95% CI 1.21-14.5), but not in HIV/HCV co-infection. Conclusion HS progresses faster and is associated with liver fibrosis progression in HIV mono-infection but not in HIV/HCV co-infection

Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors

The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiation associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of nondiabetic and T1D donors is still missing. In the present study, we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 nondiabetic autoantibody-negative, 2 nondiabetic autoantibody-positive, 8 recent-onset, and 2 long-standing T1D). In nondiabetic control donors, MDA5 was expressed both in α- and β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate of MDA5-glucagon with respect to MDA5-insulin in comparison to nondiabetic controls; such increase was more pronounced in recent-onset with respect to long-standing T1D donors. Of note, an increased colocalization rate of MDA5-glucagon was found in insulin-deficient-islets (IDIs) with respect to insulin-containing-islets (ICIs). Strikingly, we detected the presence of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, presumably due to dedifferentiation or neogenesis phenomena. These clusters were identified exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D. In conclusion, we showed that MDA5 is preferentially expressed in α-cells, and its expression is increased in recent-onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells

Non-alcoholic to metabolic associated fatty liver disease: Cardiovascular implications of a change in terminology in patients living with HIV

Background and Aims: It has recently been suggested that the definition of non-alcoholic fatty liver disease (NAFLD) be changed to Metabolic Associated FLD (MAFLD) to better reflect the complex metabolic aspects of this syndrome. We compared the ability of MAFLD and NAFLD to correctly identify high CV risk patients, sub-clinical atherosclerosis or a history of prior CV events (CVEs) in patients living with HIV (PWH). Methods: Single center, cross-sectional study of PWH on stable anti-retrovirals. NAFLD was diagnosed by transient liver elastography; published criteria were used to diagnose MAFLD (JHepatol.2020;73(1):202-209). Four mutually exclusive groups were considered: low (&lt;7.5%) vs high (&gt;7.5%) ASCVD risk, subclinical CVD (carotid IMT ≥1 mm and/or coronary calcium score &gt;100), and prior CVEs. The association of NAFLD and MAFLD with the CVD risk groups was explored via a multinominal model adjusted for age, sex, liver fibrosis, HIV duration, nadir CD4 and current CD4 cell count. Results: We included 1249 PWH (mean age 55 years, 74% men, median HIV duration 24 years). Prevalence of overweight/obesity and diabetes was 40% and 18%. Prevalence of NAFLD and MAFLD and overlapping groups are shown in Fig 1A. Fig 1B shows distribution of NAFLD/MAFLD in the 4 patient categories (p-for-trend &lt;0.001). Both MAFLD and NAFLD were significantly associated with an increased risk of CVD compared to the reference level (ASCVD&lt;7.5%) (all p-values &lt;0.004; Fig 2). Conclusions: NAFLD and MAFLD perform equally in detecting CVD or its risk. The proposed change in terminology may not help to identify PWH requiring enhanced surveillance and preventative interventions for cardiovascular disease

Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation

The loss of functional beta-cell mass in type 2 diabetes (T2D) is associated with molecular events that include beta-cell apoptosis, dysfunction and/or dedifferentiation. MicroRNA miR-184-3p has been shown to be involved in several beta-cell functions, including insulin secretion, proliferation and survival. However, the downstream targets and upstream regulators of miR-184-3p have not been fully elucidated. Here, we show reduced miR-184-3p levels in human T2D pancreatic islets, whereas its direct target CREB regulated transcription coactivator 1 (CRTC1) was increased and protects beta-cells from lipotoxicity- and inflammation-induced apoptosis. Downregulation of miR-184-3p in beta-cells leads to upregulation of CRTC1 at both the mRNA and protein levels. Remarkably, the protective effect of miR-184-3p is dependent on CRTC1, as its silencing in human beta-cells abrogates the protective mechanism mediated by inhibition of miR-184-3p. Furthermore, in accordance with miR-184-3p downregulation, we also found that the beta-cell-specific transcription factor NKX6.1, DNA-binding sites of which are predicted in the promoter sequence of human and mouse MIR184 gene, is reduced in human pancreatic T2D islets. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression. In summary, we provide evidence that the decrease in NKX6.1 expression is accompanied by a significant reduction in miR-184-3p expression and that reduction of miR-184-3p protects beta-cells from apoptosis through a CRTC1-dependent mechanism