Monocyte bioenergetics: An immunometabolic perspective in metabolic dysfunction-associated steatohepatitis.

Monocytes (Mos) are crucial in the evolution of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), and immunometabolism studies have recently suggested targeting leukocyte bioenergetics in inflammatory diseases. Here, we reveal a peculiar bioenergetic phenotype in circulating Mos of patients with MASH, characterized by high levels of glycolysis and mitochondrial (mt) respiration. The enhancement of mt respiratory chain activity, especially complex II (succinate dehydrogenase [SDH]), is unbalanced toward the production of reactive oxygen species (ROS) and is sustained at the transcriptional level with the involvement of the AMPK-mTOR-PGC-1α axis. The modulation of mt activity with dimethyl malonate (DMM), an SDH inhibitor, restores the metabolic profile and almost abrogates cytokine production. Analysis of a public single-cell RNA sequencing (scRNA-seq) dataset confirms that in murine models of MASH, liver Mo-derived macrophages exhibit an upregulation of mt and glycolytic energy pathways. Accordingly, the DMM injection in MASH mice contrasts Mo infiltration and macrophagic enrichment, suggesting immunometabolism as a potential target in MASH.

Potential Therapeutic Targets to Modulate the Endocannabinoid System in Alzheimer's Disease.

Alzheimer's disease (AD), the most common neurodegenerative disease (NDD), is characterized by chronic neuronal cell death through progressive loss of cognitive function. Amyloid beta (Aß) deposition, neuroinflammation, oxidative stress, and hyperphosphorylated tau proteins are considered the hallmarks of AD pathology. Different therapeutic approaches approved by the Food and Drug Administration can only target a single altered pathway instead of various mechanisms that are involved in AD pathology, resulting in limited symptomatic relief and almost no effect in slowing down the disease progression. Growing evidence on modulating the components of the endocannabinoid system (ECS) proclaimed their neuroprotective effects by reducing neurochemical alterations and preventing cellular dysfunction. Recent studies on AD mouse models have reported that the inhibitors of the fatty acid amide hydrolase (FAAH) and monoacylglycerol (MAGL), hydrolytic enzymes for N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), respectively, might be promising candidates as therapeutical intervention. The FAAH and MAGL inhibitors alone or in combination seem to produce neuroprotection by reversing cognitive deficits along with Aß-induced neuroinflammation, oxidative responses, and neuronal death, delaying AD progression. Their exact signaling mechanisms need to be elucidated for understanding the brain intrinsic repair mechanism. The aim of this review was to shed light on physiology and pathophysiology of AD and to summarize the experimental data on neuroprotective roles of FAAH and MAGL inhibitors. In this review, we have also included CB1R and CB2R modulators with their diverse roles to modulate ECS mediated responses such as anti-nociceptive, anxiolytic, and anti-inflammatory actions in AD. Future research would provide the directions in understanding the molecular mechanisms and development of new therapeutic interventions for the treatment of AD.

Liver fat content assessed by conventional B-mode ultrasound and metabolic profile in non-diabetic patients: Implications for clinical practice.

Introduction: Several studies have demonstrated a positive correlation between severe hepatic steatosis and metabolic alterations; however, few studies have addressed the potential association between different grades of steatosis and clinical patterns in a non-diabetic population. Methods: We conducted a cross-sectional study of 223 non-diabetic individuals. The severity of steatosis was assessed using B-mode ultrasound. We analyzed lipid and glucose profiles according to the severity of hepatic steatosis. Estimated glomerular filtration rate (eGFR) values were also recorded to investigate the potential impact of steatosis on kidney function. Results: Patients with steatosis were found to have higher insulinemia and mean values of fasting plasma glucose compared to patients without steatosis. A significant decrease in high-density lipoprotein level was observed only in patients with severe or moderate steatosis. All grades of steatosis were associated with increased triglyceride levels, which were more significant in severe steatosis. Subgroup analysis by body mass index demonstrated a significant difference between lean patients with steatosis and lean patients without steatosis for triglycerides (p = 0.002) and high-density lipoprotein levels (p = 0.019). Finally, patients diagnosed with steatosis demonstrated a higher prevalence of estimated glomerular filtration rate < 90 ml/min. Conclusion: The degree of steatosis diagnosed at ultrasound may predict glucose or lipid metabolism disorders and a decline in kidney function in a non-diabetic population.

Metabolic reprogramming in inflammatory microglia indicates a potential way of targeting inflammation in Alzheimer's disease.

Microglia activation drives the pro-inflammatory activity in the early stages of Alzheimer's disease (AD). However, the mechanistic basis is elusive, and the hypothesis of targeting microglia to prevent AD onset is little explored. Here, we demonstrated that upon LPS exposure, microglia shift towards an energetic phenotype characterised by high glycolysis and high mitochondrial respiration with dysfunction. Although the activity of electron transport chain (ETC) complexes is boosted by LPS, this is mostly devoted to the generation of reactive oxygen species. We showed that by inhibiting succinate dehydrogenase (SDH) with dimethyl malonate (DMM), it is possible to modulate the LPS-induced metabolic rewiring, facilitating an anti-inflammatory phenotype. DMM improves mitochondrial function in a direct way and by reducing LPS-induced mitochondrial biogenesis. Moreover, the block of SDH with DMM inhibits the recruitment of hypoxia inducible-factor 1 α (HIF-1α), which mediates the induction of glycolysis and cytokine expression. Similar bioenergetic alterations were observed in the microglia isolated from AD mice (3xTg-AD), which present high levels of circulating LPS and brain toll-like receptor4 (TLR4). Moreover, this well-established model of AD was used to show a potential effect of SDH inhibition in vivo as DMM administration abrogated brain inflammation and modulated the microglia metabolic alterations of 3xTg-AD mice. The RNA-sequencing analysis from a public dataset confirmed the consistent transcription of genes encoding for ETC subunits in the microglia of AD mice (5xFAD). In conclusion, TLR4 activation promotes metabolic changes and the pro-inflammatory activity in microglia, and SDH might represent a promising therapeutic target to prevent AD development.

Liver Ultrasound Elastography in Non-Alcoholic Fatty Liver Disease: A State-of-the-Art Summary.

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease which is currently the most common hepatic disorder affecting up to 38% of the general population with differences according to age, country, ethnicity and sex. Both genetic and acquired risk factors such as a high-calorie diet or high intake of saturated fats have been associated with obesity, diabetes and, finally, NAFLD. A liver biopsy has always been considered essential for the diagnosis of NAFLD; however, due to several limitations such as the potential occurrence of major complications, sampling variability and the poor repeatability in clinical practice, it is considered an imperfect option for the evaluation of liver fibrosis over time. For these reasons, a non-invasive assessment by serum biomarkers and the quantification of liver stiffness is becoming the new frontier in the management of patients with NAFLD and liver fibrosis. We present a state-of-the-art summary addressing the methods for the non-invasive evaluation of liver fibrosis in NAFLD patients, particularly the ultrasound-based techniques (transient elastography, ARFI techniques and strain elastography) and their optimal cut-off values for the staging of liver fibrosis.

The urotensin-II receptor: A marker for staging and steroid outcome prediction in ulcerative colitis.

BACKGROUND: Urotensin-II receptor- (UTR) related pathway exerts a key-role in promoting inflammation. The aim was to assess the relationship between UTR expression and clinical, endoscopic and biochemical severity of ulcerative colitis (UC), exploring its predictivity of intravenous (iv) steroid administration therapeutic outcome. METHODS: One-hundred patients with first diagnosis of UC and 44 healthy subjects were enrolled. UTR expression was assessed by qPCR, Western Blot (WB) and immunohistochemistry (IHC). Clinical, endoscopic and histological activity of UC were evaluated by using Truelove and Witts (T&W) severity index, Mayo Endoscopic Score (MES), and Truelove and Richards Index (TRI). The partial and full Mayo scores (PMS and FMS) were assessed to stage the disease. RESULTS: The UTR expression, resulted higher in the lesioned mucosa of UC patients in comparison to healthy subjects (p < .0001 all). Direct relationship between UTR (mRNA and protein) expression and disease severity assessment (T&W, PMS, MES and TRI) was highlighted (p < .0001 all). UTR expression resulted also higher in the 72 patients requiring iv steroids administration compared to those who underwent alternative medications, (p < .0001). The 32 steroid-non-responders showed an increased UTR expression (WB, IHC and qPCR from lesioned mucosa), compared to 40 steroid-responders (p: .0002, .0001, p < .0001 respectively). The predictive role of UTR expression (p < .05) on the negative iv steroids administration therapeutic outcome was highlighted and ROC curves identified the thresholds expressing the better predictive performance. CONCLUSIONS: UTR represents a promising inflammatory marker related to clinical, endoscopic, and histological disease activity as well as a predictive marker of steroid administration therapeutic outcome in the UC context.

Prevalence and risk factors for hospital-acquired anemia in internal medicine patients: learning from the "less is more" perspective.

Hospital-acquired anemia is defined as a new-onset anemia in hospitalized patients who have a normal hemoglobin level at admission. Its prevalence is unknown and most studies published on this topic have been conducted in intensive care unit patients with limited applicability to less acute settings, such as internal medicine wards. We conducted a retrospective study and enrolled 129 patients who were admitted to an Internal Medicine Unit between October 2021 and February 2022. The median value of phlebotomy during hospitalization was 46 ml (IQR 30-72 ml), whereas the median length of hospital stay was 9 days (IQR 5-13 days). The median value of hemoglobin reduction was -0.63 g/dl (p < 0.001) and the maximum value of drop in hemoglobin value was -2.6 g/dl. All patients who experienced a phlebotomy > 85 ml had a hemoglobin reduction > 0.6 g/dl. 20.9% of patients developed anemia during the hospital stay (7% moderate and 13.9% mild). No cases of severe anemia were observed. The volume of blood drawn during the hospital stay and the Hb value on admission were the only two variables statistically associated with the development of anemia, whereas gender, age, and chronic diseases, such as diabetes, history of cancer, or heart failure, were not. Strategies, such as elimination of unnecessary laboratory tests and the use of smaller tubes for blood collection, are needed to reduce the volume of iatrogenic blood loss and avoid blood wastage occurring during hospitalization in internal medicine patients.

Exploring the Relationship between Epicardial Fat Thickness and Coronary Revascularization: Implications for Cardiovascular Health.

BACKGROUND: this study aimed to assess the complex relationship between EAT thickness, as measured with echocardiography, and the severity of coronary artery disease (CAD). We investigated whether individuals with higher EAT thickness underwent coronary revascularization. Subsequently, we conducted a three-year follow-up to explore any potential modifications in EAT depots post-angioplasty. METHODS: we conducted a prospective and retrospective cross-sectional observational study involving 150 patients consecutively referred for acute coronary syndrome, including ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina. Upon admission (T0), all patients underwent coronary angiography to assess the number of pathologic coronary vessels. Percutaneous transluminal coronary angioplasty (PTCA) was performed based on angiogram results if indicated. The sample was categorized into two groups: non-revascularized (no-PTCA) and revascularized (PTCA). Transthoracic echocardiograms to measure epicardial fat thickness were conducted at admission (T0) and after a 3-year follow-up (T1). RESULTS AND CONCLUSIONS: findings revealed a positive correlation between EAT thickness and the severity of coronary artery disease (CAD), with patients undergoing PTCA showing decreased EAT thickness after three years. Echocardiography demonstrated reliability in assessing EAT, offering potential for risk stratification. The study introduces a cut-off value of 0.65 cm as a diagnostic tool for cardiovascular risk. Incorporating EAT measurements into clinical practice may lead to more precise risk stratification and tailored treatment strategies, ultimately reducing the burden of cardiovascular disease.

Pseudocirrhosis and portal hypertension in patients with metastatic cancers: a systematic review and meta-analysis.

Pseudocirrhosis is a clinical and radiological entity mimicking liver cirrhosis in patients without a history of chronic liver disease. We performed a systematic review and meta-analysis of the current literature to evaluate the state-of-the-art and investigate the epidemiology and clinical features of pseudocirrhosis. We searched PubMed, Web of Science and Scopus for literature published until February 28, 2022. We included in the final analysis 62 articles (N = 389 patients): 51 case reports (N = 64 patients), 5 case series (N = 35 patients) and 6 observational studies (N = 290 patients). About 80% of patients included in the case reports and case series had breast cancer. Most patients had at least one clinical sign of portal hypertension and ascites was the most common clinical manifestation of portal hypertension. The median time from pseudocirrhosis to death was 2 months (IQR 1-7 months). Alkylating agents and antimitotics were the most common classes of anticancer drugs reported in our study population. Notably, about 70% of patients received three or more anticancer drugs. Finally, pseudocirrhosis is a condition that occurs in patients with hepatic metastases and may have a negative impact on survival and clinical management of patients because of the potential development of portal hypertension and its complications.

Eradication of HCV by direct antiviral agents restores mitochondrial function and energy homeostasis in peripheral blood mononuclear cells.

Hepatitis C virus (HCV) adopts several immune evasion mechanisms such as interfering with innate immunity or promoting T-cell exhaustion. However, the recent direct-antiviral agents (DAAs) rapidly eliminate the virus, and the repercussions in terms of immune system balance are unknown. Here we compared the PBMCs transcriptomic profile of patients with HCV chronic infection at baseline (T0) and 12 weeks after the end of the therapy (SVR12) with DAAs. 3862 genes were differently modulated, identifying oxidative phosphorylation as the top canonical pathway differentially activated. Therefore, we dissected PBMCs bioenergetic profile by analyzing mitochondrial respiration and glycolysis at 4 timepoints: T0, 4 weeks of therapy, end of therapy (EoT), and SVR12. Maximal and reserve respiratory capacity considerably increased at EoT, persisting until SVR12. Notably, over time a significant increase was observed in respiratory chain (RC) complexes protein levels and the enzymatic activity of complexes I, II, and IV. Mitochondrial-DNA integrity improved over time, and the expression of mitochondrial biogenesis key regulators such as TFAM, Nrf-1, and PPARGC1A significantly increased at SVR12; hence, RC complexes synthesis and mitochondrial respiration were supported after treatment. HCV clearance with DAAS profoundly changed PBMCs bioenergetic profile, suggesting the immunometabolism study as a new approach to the understanding of viral immune evasion mechanisms and host adaptations during infections and therapies.

Recovery of Bacteroides thetaiotaomicron ameliorates hepatic steatosis in experimental alcohol-related liver disease.

Alcohol-related liver disease (ALD) is a major cause of liver disease and represents a global burden, as treatment options are scarce. Whereas 90% of ethanol abusers develop alcoholic fatty liver disease (AFLD), only a minority evolves to steatohepatitis and cirrhosis. Alcohol increases lipogenesis and suppresses lipid-oxidation implying steatosis, although the key role of intestinal barrier integrity and microbiota in ALD has recently emerged. Bacteroides thetaiotaomicron (Bt) is a prominent member of human and murine intestinal microbiota, and plays important functions in metabolism, gut immunity, and mucosal barrier. We aimed to investigate the role of Bt in the genesis of ethanol-induced liver steatosis. Bt DNA was measured in feces of wild-type mice receiving a Lieber-DeCarli diet supplemented with an increase in alcohol concentration. In a second step, ethanol-fed mice were orally treated with living Bt, followed by analysis of intestinal homeostasis and histological and biochemical alterations in the liver. Alcohol feeding reduced Bt abundance, which was preserved by Bt oral supplementation. Bt-treated mice displayed lower hepatic steatosis and triglyceride content. Bt restored mucosal barrier and reduced LPS translocation by enhancing mucus thickness and production of Mucin2. Furthermore, Bt up-regulated Glucagon-like peptide-1 (GLP-1) expression and restored ethanol-induced Fibroblast growth factor 15 (FGF15) down-regulation. Lipid metabolism was consequently affected as Bt administration reduced fatty acid synthesis (FA) and improved FA oxidation and lipid exportation. Moreover, treatment with Bt preserved the mitochondrial fitness and redox state in alcohol-fed mice. In conclusion, recovery of ethanol-induced Bt depletion by oral supplementation was associated with restored intestinal homeostasis and ameliorated experimental ALD. Bt could serve as a novel probiotic to treat ALD in the future.

Genetic Polymorphisms and Clinical Features in Diabetic Patients With Fatty Liver: Results From a Single-Center Experience in Southern Italy.

Genetic background may be involved in the promotion and progression of non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that the single nucleotide polymorphisms (SNPs) may be associated with the specific clinical features in the patients with hepatic steatosis; however, data on the patients with diabetes from Southern Italy are lacking. We enrolled 454 patients and 260 of them had type 2 diabetes. We studied the PNPLA3 rs738409, LPIN1 rs13412852, KLF6 rs3750861, SOD2 rs4880, TM6SF2 rs58542926, and ZNF624 rs12603226 SNPs and their distribution in the study population. Lipid profile, liver stiffness, and kidney function were also studied to understand the potential role of the SNPs in the development of clinical phenotypes. No differences were observed in the distribution of polymorphisms between the diabetic and non-diabetic subjects. Carriers of risk allele G for PNPLA3 rs738409 SNP showed a lower mean value of serum triglycerides and a higher liver stiffness. Risk allele for KLF6 rs3750861 and SOD2 rs4880 polymorphism had a lower estimated glomerular filtration rate (eGFR) value, whereas no differences in the glucose and glycated hemoglobin level were observed in the subgroups by the different genotypes. Genetic polymorphisms are useful to identify the patients at higher risk of development of liver fibrosis and lower eGFR values in the patients with diabetes and NAFLD. Their use in clinical practice may help the clinicians to identify the patients who require a more strict follow-up program.

Serum lipid profile in HCV patients treated with direct-acting antivirals: a systematic review and meta-analysis.

Although direct-acting antivirals are very effective and safe drugs, several authors have reported the alteration of lipid profile during and after anti-HCV therapy suggesting a potential impact on the risk of cardiovascular events. We performed a systematic review and meta-analysis of observational studies to investigate the magnitude and temporal trend of lipid profile changes in DAA treated patients. All selected studies included data on lipid profile before starting therapy and at least one follow-up assessment during or after antiviral treatment. We identified 14 studies (N = 1537 patients) after removing duplicates. Pooled data showed an increase in total cholesterol 4 weeks after starting therapy (+ 15.86 mg/dl; 95% CI + 9.68 to 22.05; p < 0.001) and 12 weeks after treatment completion (+ 17.05 mg/dl; 95% CI + 11.24 to 22.85; p < 0.001). LDL trend was similar to the total cholesterol change in overall analysis. A mean increase in HDL-cholesterol of 3.36 mg/dl (95% CI + 0.92 to 5.79; p = 0.07) was observed after 12 weeks of treatment, whereas at SVR24 HDL difference was + 4.34 mg/dl (95% CI + 1.40 to 7.28; p = 0.004).Triglycerides did not show significant changes during treatment and after treatment completion. DAAs induce mild lipid changes in chronic hepatitis C patients treated with DAAs, which may persist after treatment completion.

Analysis of hepatic stiffness after viral eradication in a population with chronic hepatitis C treated with DAAs

Introduction and objectives: Despite chronic hepatitis C (CHC) is still a global burden as the high morbidity and mortality, the recently approved direct-acting antivirals (DAAs) permit a very high rate of sustained virologic response (SVR) in these patients. The clinical improvement due to viral eradication is being documented, however it is not clear why a subset of patients does not benefit in terms of fibrosis regression or hepatocellular carcinoma (HCC) development. Aim of the study was to assess the hepatic stiffness regression at SVR24 and detect factors impacting stiffness course.Patients and methodsHepatic stiffness assessed by acoustic radiation force impulse (ARFI) and anthropometric- and biochemical parameters were retrospectively collected by 166 CHC patients treated with DAAs, form baseline and SVR24.ResultsViral eradication significantly improved overall hepatic stiffness and other related hepatitis hallmarks such as ALT, AST, γGT, platelets count, AST to Platelets ratio Index (APRI), total- and LDL cholesterol. The multiple regression analysis showed that patients with baseline glucose > 110mg/dl presented a stiffness regression significantly lower when compared to low glucose patients (<110mg/dl), moreover baseline HbA1c strongly correlated with DeltaStiffness. 7 patients (4.2%) developed HCC and importantly, presented hyperglycaemia and no stiffness regression nor platelets count recover.ConclusionsAlthough viral eradication with DAAs entails overall benefits, glycaemic decompensation negatively affects fibrosis regression and probably facilitates HCC development. (AU)

Introducción y objetivos: Aunque la hepatitis C crónica (CHC) sigue siendo una carga global debida a la alta morbilidad y mortalidad, los antivirales de acción directa (AAD) recientemente aprobados, permiten un índice muy alto de respuesta virológica sostenida (RVS) en estos pacientes. La mejoría clínica debida a la erradicación viral está siendo documentada, pero no está claro por qué un subconjunto de pacientes no se beneficia en términos de regresión de fibrosis o desarrollo de carcinoma hepatocelular (HCC). El objetivo de este estudio fue evaluar la regresión de la rigidez hepática en SVR24 y detectar los factores que afectan el curso de la rigidez.Pacientes y métodosLa rigidez hepática evaluada por la radiación acústica de la fuerza de impulso (ARFI) y los parámetros antropométricos y bioquímicos fueron recolectados retrospectivamente por 166 pacientes con CHC tratados con ADD, desde el punto de partida y SVR24.ResultadosLa erradicación viral mejoró significativamente la rigidez hepática general y otros signos relacionados con la hepatitis, como ALT, AST, γGT, conteo de plaquetas, índice da razão AST/plaquetas (APRI), colesterol total y LDL. El análisis de regresión múltiple mostró que los pacientes con glucosa basal >110 mg/dL tuvieron una regresión de rigidez significativamente inferior en comparación con los pacientes con glucosa baja (<110 mg/dL), además la HbA1c de referencia se correlacionó fuertemente con DeltaStiffness. Siete pacientes (4,2%) desarrollaron CHC y, lo que es más importante, presentaron hiperglucemia y no hubo regresión de rigidez ni recuperación del conteo de plaquetas.ConclusionesA pesar de que la erradicación viral con AAD conlleva diversos beneficios, la descompensación glucémica afecta negativamente la regresión de la fibrosis y probablemente facilita el desarrollo de CHC. (AU)

A Novel Nutraceuticals Mixture Improves Liver Steatosis by Preventing Oxidative Stress and Mitochondrial Dysfunction in a NAFLD Model.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease globally, and represents a health care burden as treatment options are very scarce. The reason behind the NAFLD progression to non-alcoholic steatohepatitis (NASH) is not completely understood. Recently, the deficiency of micronutrients (e.g., vitamins, minerals, and other elements) has been suggested as crucial in NAFLD progression, such that recent studies reported the potential hepatic antioxidant properties of micronutrients supplementation. However, very little is known. Here we have explored the potential beneficial effects of dietary supplementation with FLINAX, a novel mixture of nutraceuticals (i.e., vitamin E, vitamin D3, olive dry-extract, cinnamon dry-extract and fish oil) in a NAFLD model characterized by oxidative stress and mitochondrial function impairment. Steatosis was firstly induced in Wistar rats by feeding with a high-fat/high-cholesterol diet for 4 weeks, and following this the rats were divided into two groups. One group (n = 8) was treated for 2 weeks with a normal chow-diet, while a second group (n = 8) was fed with a chow-diet supplemented with 2% FLINAX. Along with the entire experiment (6 weeks), a third group of rats was fed with a chow-diet only as control. Statistical analysis was performed with Student's T test or one-way ANOVA followed by post-hoc Bonferroni test when appropriate. Steatosis, oxidative stress and mitochondrial respiratory chain (RC) complexes activity were analyzed in liver tissues. The dietary supplementation with FLINAX significantly improved hepatic steatosis and lipid accumulation compared to untreated rats. The mRNA and protein levels analysis showed that CPT1A and CPT2 were up-regulated by FLINAX, suggesting the enhancement of fatty acids oxidation (FAO). Important lipoperoxidation markers (i.e., HNE- and MDA-protein adducts) and the quantity of total mitochondrial oxidized proteins were significantly lower in FLINAX-treated rats. Intriguingly, FLINAX restored the mitochondrial function, stimulating the activity of mitochondrial RC complexes (i.e., I, II, III and ATP-synthase) and counteracting the peroxide production from pyruvate/malate (complex I) and succinate (complex II). Therefore, the supplementation with FLINAX reprogrammed the cellular energy homeostasis by restoring the efficiency of mitochondrial function, with a consequent improvement in steatosis.

Temporal profile of SARS-CoV-2 viral load in posterior nasopharyngeal samples: Analysis of 944 patients in Apulia, Italy.

OBJECTIVES: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has heavily impacted Italy. The government's restriction measures have attenuated the burden on hospitals. The association of high viral replication with disease severity suggests the potential for lower viral load in milder clinical presentations. METHODS: The reverse-transcription-polymerase-chain-reaction (RT-PCR) profile of 944 consecutive, non-replicate, positive retropharyngeal swabs was collected from 3 March to 8 June 2020 to investigate the temporal profile of SARS-CoV-2 viral load in the region of Capitanata, Apulia. Cycle threshold (Ct) values of 3 targets (N [nucleocapsid protein], E [envelope protein] and RdRP [RNA-dependent RNA-polymerase]) were analysed. RESULTS: The median Ct values of the 3 targets increased considerably over the study period, showing a progressive and constant weekly change. The negative detection rate of E and RdRP increased over time. These data suggest that SARS-CoV-2 viral load progressively decreased along the outbreak course. During the first epidemic peak (March and April) the viral load among patients >80-years was significantly higher than for younger subjects. However, in May this age-dependent difference disappeared, underlying viral load reduction in the elderly. CONCLUSIONS: An attenuation of viral transmission or pathogenicity during the epidemic course is suggested, likely due to restriction measures, although viral factors might also be considered.

Direct-acting antivirals improve kidney function in diabetic patients with HCV infection and chronic kidney disease.

After direct-acting antiviral (DAA) approval, a larger number of diabetic patients with chronic HCV infection have been treated. Cardiovascular risk and insulin resistance significantly change after successful clearance of HCV. Therefore, HCV therapy could potentially improve diabetes microvascular complications including nephropathy. We assessed kidney function after antiviral treatment completion in diabetic (N = 96) and non-diabetic patients (N = 187). Assessment of renal function was performed by serum creatinine and estimated glomerular filtration rate (eGFR) at baseline, at treatment completion and 12 weeks after treatment. Subgroup analysis by age, DAA regimen and eGFR stage at baseline was performed. Serum creatinine did not change significantly at any time whereas eGFR significantly improved during time in diabetic patients (baseline 83.7 ml/min/1.73 m2 vs 102.6 ml/min/1.73 m2 at 12 weeks after treatment completion; p = 0.028). Subgroup analysis showed that the improvement was observed particularly in old people with eGFR < 60 ml/min/1.73 m2. Antiviral regimens did not impact the eGFR values. Sixteen percent of diabetic patients improved their kidney function during treatment (vs 14.4% of non-diabetic patients) showing a one category change in eGFR. No acute kidney injury events were recorded in our cohort. Our study suggests that DAAs improve renal function in HCV diabetic patients with eGFR < 60 ml/min/1.73 m2 or aged ≥ 65 years independently from antiviral regimen.

Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression.

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and has become the major cause of chronic liver disease, especially in western countries. NAFLD encompasses a wide spectrum of hepatic histological alterations, from simple steatosis to steatohepatitis and cirrhosis with a potential development of hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and fibrosis. Several studies reported that insulin resistance, redox unbalance, inflammation, and lipid metabolism dysregulation are involved in NAFLD progression. However, the mechanisms beyond the evolution of simple steatosis to NASH are not clearly understood yet. Recent findings suggest that different oxidized products, such as lipids, cholesterol, aldehydes and other macromolecules could drive the inflammation onset. On the other hand, new evidence indicates innate and adaptive immunity activation as the driving force in establishing liver inflammation and fibrosis. In this review, we discuss how immunity, triggered by oxidative products and promoting in turn oxidative stress in a vicious cycle, fuels NAFLD progression. Furthermore, we explored the emerging importance of immune cell metabolism in determining inflammation, describing the potential application of trained immune discoveries in the NASH pathological context.

Management of intermediate-stage hepatocellular carcinoma in the elderly with transcatheter arterial chemoembolization failure: Retreatment or switching to systemic therapy?

BACKGROUND: Transcatheter Arterial chemoembolization (TACE) is the first-line option for the intermediate-stage hepatocellular carcinoma. Guidelines do not define the number of TACE sessions to be repeated before stopping treatment and switching to sorafenib. METHODS: We retrospectively analysed 76 patients aged ≥65 years who were treated by multiple TACE sessions (re-TACE group; N = 36 patients) or one TACE session followed by sorafenib (TACE/Sorafenib group; N = 40 patients). The primary outcome was the overall survival (Kaplan-Meier analysis and log-rank test). RESULTS: Median overall survival was 320 days (range: 70-420 days) in re-TACE subgroup and 285 days (range: 50-368 days) in TACE/Sorafenib subgroup without significant differences between the two groups (log-rank test P = .72; HR = 0.87; 95% IC 0.41-1.87). The survival rate at one year was 43.6% and 32% in the re-TACE and in the TACE/sorafenib groups (P = .12), respectively. Subgroup analysis by gender, number of nodules at baseline and etiology of liver cirrhosis was performed but no differences were found. No statistical difference was observed in the frequency of side effects, but sorafenib was associated with severe diarrhoea in most patients requiring dose reduction. CONCLUSION: In our study including HCC patients aged ≥65 years, no differences in survival rate and side effects were found between patients Retreated with further TACE sessions and patients with treatment stage migration to sorafenib after first TACE failure. We included in our analysis a small study population; therefore, larger prospective studies are needed to confirm these findings.

Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans.

OBJECTIVE: Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD. DESIGN: An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models. RESULTS: Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis. CONCLUSION: Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.