Evaluating cardiovascular risk in metabolic steatosis with precision medicine non-invasive approaches: insights from a cohort study.

Metabolic associated steatotic liver disease (MASLD) is the most common liver condition. It is associated with increased liver-related morbidity and mortality, and also with high risk of cardiovascular events (CVD), representing itself an independent risk factor for it. This makes MASLD a presentation of high interest for internal medicine, also because of its association with metabolic syndrome (MetS). It is crucial to assess its risks in a noninvasive way. With the aim of finding specific risk profiles for CVD development in MASLD by performing a noninvasive assessment of: (1) preclinical signs of endothelial dysfunction (ED); (2) clinical assessment of CVD risk by Framingham Heart Risk Score (FHRs); (3) genomic characterization of MASLD associated polymorphisms; (4) specific untargeted metabolomic profiles, we enrolled 466 MASLD patients non-invasively classified in 4 group of liver fibrosis severity (group-A: low-fibrosis risk, group-B: high-fibrosis risk, group-C: MASLD-cirrhosis, group-D: MASLD-HCC) and 73 healthy controls. FHRs was similar in controls and low-fibrosis group and significantly higher in high-fibrosis patients, cirrhosis, and HCC, increasing among classes. At a multivariable regression, FHRs was associated with liver disease severity and diabetes. 38.2% of patients had altered EndoPAT, resembling ED. Patients with high FHRs (> 40%) and ED had different metabolomics compared to those without ED. Our study reveals that a deep, non-invasive characterization of MASLD patients through precision medicine approaches (untargeted metabolomics, SNPs, ED assessment) was able to show a peculiar pattern in MASLD patients with increased CVD risk, mostly correlated with liver disease severity.

The influence of acute lifestyle changes on NAFLD evolution in a multicentre cohort: a matter of body composition.

BACKGROUND: Unhealthy lifestyles represent a key element fueling Non-alcoholic fatty liver disease (NAFLD) onset and worsening. We aimed to evaluate the effects of forced acute lifestyle changes on NAFLD evolution. METHODS: 187 NAFLD patients were followed two years pre- and two years during the lockdown social restrictions in three Italian medical centers. For each patient, biochemical, clinical, non-invasive liver fibrosis, nutritional, and body composition data were collected. RESULTS: An increase in fats and carbohydrate intake associated with impaired weekly physical activity during the lockdown was demonstrated as well as an increase in body mass index and waist-hip-ratio (p < 0.0001 for all). Total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, insulin, homeostatic model assessment for insulin resistance, and transaminases worsened during the lockdown (glucose: p = 0.0007; p < 0.0001 for the others). Moreover, NAFLD fibrosis score, liver stiffness, and controlled attenuation parameter were also impaired during the same period (p < 0.0001 for all). The bioelectrical impedance analysis (BIA) evidenced an increase of fat mass (FM), and a reduction of free fat mass (FFM) and body cell mass (BCM) (p < 0.0001 for all). The lockdown overall hepatocellular carcinoma (HCC) and Milan-out HCC occurrence revealed Hazard Ratio (HR): 2.398, 95% Confidence Interval (CI):1.16-5, p = 0.02, and HR:5.931, CI:2-17.6, p = 0.008 respectively. A liver disease stage and comorbidities independent association between both the assessed outcomes and body composition analysis in terms of mean values and variation (T1-T2 Δ) was demonstrated. CONCLUSIONS: The acute lifestyle changes impacted NAFLD evolution via body composition modifications negatively influencing the HCC occurrence.

Gut-Liver Axis Dysregulation in Portal Hypertension: Emerging Frontiers.

Portal hypertension (PH) is a complex clinical challenge with severe complications, including variceal bleeding, ascites, hepatic encephalopathy, and hepatorenal syndrome. The gut microbiota (GM) and its interconnectedness with human health have emerged as a captivating field of research. This review explores the intricate connections between the gut and the liver, aiming to elucidate how alterations in GM, intestinal barrier function, and gut-derived molecules impact the development and progression of PH. A systematic literature search, following PRISMA guidelines, identified 12 original articles that suggest a relationship between GM, the gut-liver axis, and PH. Mechanisms such as dysbiosis, bacterial translocation, altered microbial structure, and inflammation appear to orchestrate this relationship. One notable study highlights the pivotal role of the farnesoid X receptor axis in regulating the interplay between the gut and liver and proposes it as a promising therapeutic target. Fecal transplantation experiments further emphasize the pathogenic significance of the GM in modulating liver maladies, including PH. Recent advancements in metagenomics and metabolomics have expanded our understanding of the GM's role in human ailments. The review suggests that addressing the unmet need of identifying gut-liver axis-related metabolic and molecular pathways holds potential for elucidating pathogenesis and directing novel therapeutic interventions.

From Non-Alcoholic Steatohepatitis (NASH) to Hepatocellular Carcinoma (HCC): Epidemiology, Incidence, Predictions, Risk Factors, and Prevention.

Non-alcoholic fatty liver disease (NAFLD) affects up to a quarter of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. The incidence of NASH is projected to increase by up to 56% over the next 10 years. There is growing epidemiological evidence that NAFLD has become the fastest-growing cause of hepatocellular carcinoma (HCC) in industrialized countries. The annual incidence of HCC varies between patients with NASH cirrhosis and patients with noncirrhotic NAFLD. In this review, NAFLD/NASH-associated HCC will be described, including its epidemiology, risk factors promoting hepatocarcinogenesis, and management of HCC in patients with obesity and associated metabolic comorbidities, including preventive strategies and therapeutic approaches to address this growing problem.

Country-Wide HCV Elimination Strategies Need to Reach Older Patients in the General Population: The Italian Experience.

HCV infection is still a major burden worldwide, and most countries are not on track to meet the WHO 2030 elimination goal. The current challenge is to identify individuals to be treated. In this study, we will describe the trend of new DAA prescriptions and the changes over time in terms of the characteristics of patients starting antiviral therapy in our unit. Data of 1646 hepatitis C patients who started therapy during the period of 2015-2022 regarding annual number of prescriptions, age, gender, nationality, HCV genotype, provenance, and liver disease severity were analyzed. We observed a peak in the number of new prescriptions in 2018 and a downward trend starting in 2019. Patients from the general population, centers for addictions, and prison differed significantly. The mean age in the general population remained above 60 years, the percentage of patients from centers for addictions and prison increased and, after 2016, there was no significant change in the percentage of patients with F3-F4 fibrosis. As HCV screening and linkage-to-care pathways seem to be already well implemented and successful in centers for addictions and in prisons, efforts need to be focused on those of older age in the general population. To carry this out, the more structured involvement of different health professionals must be figured out.

Glecaprevir/Pibrentasvir is safe and effective in Italian patients with chronic hepatitis C aged 75 years or older: A multicentre study.

BACKGROUND: Glecaprevir and Pibrentasvir (G/P) determine high rates of sustained virological response (SVR) with optimal safety profile in patients with chronic hepatitis C virus (HCV) infection. The efficacy and safety of G/P in Caucasian patients aged 75 years and older have not been widely analysed. METHODS: This is a retrospective multicentre real-world study enrolling all consecutive patients 75 years and older who received G/P between October 2017 and January 2022 at five referral centres in Italy. SVR was analysed by intention-to-treat (ITT) and per-protocol analyses (PP). RESULTS: A total of 570 patients met the inclusion criteria and were analysed: mean age was 80 (75-97) years, 356 (62%) were females, 52% (298/570) had HCV-1, 44% (252/570) had HCV-2 and 137 (24%) patients had liver cirrhosis. Four hundred and sixty-three (81%) patients were taking at least one concomitant drug, with 144 (25%) taking ≥5 concomitant drugs. G/P was given for 8 weeks in 488 patients (86%). During treatment, 48 patients (8%) reported side effects, with 10 (2%) patients discontinuing treatment prematurely. Two patients developed treatment-unrelated serious adverse events. Overall, the SVR rate was 97.9% (558/570) by ITT analysis and 99.6% (558/560) by PP analysis. SVR rates remained consistently high among subgroup analysis stratified by genotype, treatment duration, fibrosis stage and concomitant medications. CONCLUSIONS: Treatment with G/P achieved 97.9% SVR rates in HCV patients older than 75 years of age. Safety was optimal with only 2% of patients discontinuing early.

Alcoholic Consumption of Young Italians During the SARS-CoV-2 Pandemic.

BACKGROUND: The international health emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which, at the end of 2019, hit the world, forced the governments of all countries to adopt stringent restrictive measures to contain the spread of the virus. Several studies have revealed worsening levels of anxiety, depression and perceived stress related to these restrictions and the resulting lifestyle changes. Some studies have also confirmed the presence of a relationship between SARS-CoV-2-related emotional distress and drinking behavior. Indeed, is a wellknown fact that alcohol consumption is one of the behavioral strategies used to reduce negative emotional states. However, it was documented that young people developed different responses to alcohol use during the pandemic than adults. OBJECTIVE: The aim of this work was to investigate the consumption habits of young Italians and how the consumption and purchase of alcoholic beverages have changed following the pandemic. New ways of drinking alcohol were also interesting to observe, such as online. METHODS: Young people between 18 and 35 years old were subjected to an anonymous questionnaire of 22 questions on the adoption of forms of behavior at risk through alcohol consumption, the quantity and occasions of preferential consumption, and on the methods and quantities of alcoholic beverage purchase, before and during the SARS-CoV-2 pandemic. The subjects who declared themselves "non-drinkers" were not included in the statistical survey. RESULTS: About 33% of the enrolled "drinkers" (268/823), adopted risky forms of alcoholic behavior. Males reported a higher average habit of drinking wine or alcohol (M = 1.9953 ± 1.39743, F = 1.7373 ± 1.36688, p <0.005); an increased frequency of drinking (M = 2.3025 ± 0.80610 F = 2.0494 ± 0.75043 p <0.001); a higher average number of drinks consumed (M = 1.5182 ± 0.85646, F = 1.2618 ± 0.53292, p <0.001) and binge drinking to the greatest extent (M = 1.1933 ± 0.96522 F = 0.8176 ± 0.85446 p <0.001). Education and employment were significantly correlated with the frequency of alcohol consumption (r = 0.107 p <0.005 and r = 0.120 p = 0.001 respectively). Subjects reported buying alcoholic beverages during the pandemic with a frequency of "less than once a month" (N = 291, 35.36%) and mainly in shops (N = 556, 67.56%), while before the pandemic they mainly bought alcohol once a week (N = 431, 52.37%) and predominantly in bars / clubs (N = 619, 75.21%). New ways of drinking alcohol such as online drinking, have not been significantly identified. CONCLUSION: A change in alcohol consumed and alcohol purchased before and during the SARSCoV- 2 pandemic was revealed.

Optimizing systemic therapy for advanced hepatocellular carcinoma: the key role of liver function.

The number of effective systemic therapies for the treatment of advanced hepatocellular carcinoma (HCC) is rapidly increasing, and the advent of immunotherapy has changed the treatment paradigm for these patients, leading to significantly improved survival outcomes. However, many patients with HCC will continue to receive tyrosine kinase inhibitors, partly because of contraindications to immune checkpoint inhibitors. Currently, the best sequential first- and second-line systemic treatment remains elusive. Maintenance of optimal liver function is crucial, it is likely to impinge on temporary or permanent treatment discontinuation, and should also be considered when defining the treatment sequence. Hepatic decompensation, which does not always coincide with disease progression, is part of this complex dynamically evolving system, and must be promptly recognized and adequately managed to allow the patient to continue in the therapeutic course. The purpose of this review is to highlight and summarize the evidence on the efficacy and safety of systemic agents, with a focus on the impact of underlying cirrhosis, and to suggest new clinical outcomes for randomized controlled trials for advanced HCC to better assess the net health benefit in this specific setting.

A prospective study of direct-acting antiviral effectiveness and relapse risk in HCV cryoglobulinemic vasculitis by the Italian PITER cohort.

BACKGROUND AND AIMS: Mixed cryoglobulinemia is the most common HCV extrahepatic manifestation. We aimed to prospectively evaluate the cryoglobulinemic vasculitis (CV) clinical profile after a sustained virologic response (SVR) over a medium-term to long-term period. APPROACH AND RESULTS: Direct-acting antiviral-treated cryoglobulinemic patients, consecutively enrolled in the multicentric Italian Platform for the Study of Viral Hepatitis Therapy cohort, were prospectively evaluated. Cumulative incidence Kaplan-Meier curves were reported for response, clinical deterioration, relapse and relapse-free survival rates. Cox regression analysis evaluated factors associated with different outcomes. A clinical response was reported in at least one follow-up point for 373 of 423 (88%) patients with CV who achieved SVR. Clinical response increased over time with a 76% improvement rate at month 12 after the end of treatment. A full complete response (FCR) was reached by 164 (38.8%) patients in at least one follow-up point. CV clinical response fluctuated, with some deterioration of the initial response in 49.6% of patients (median time of deterioration, 19 months). In patients who achieved FCR and had an available follow-up (137 patients) a relapse was observed in 13% and it was transient in 66.7% of patients. The rate of patients without any deterioration was 58% and 41% at 12 and 24 months, respectively. After achieving SVR, a clinical nonresponse was associated with older age and renal involvement; a clinical deterioration/relapse was associated with high pretreatment rheumatoid factor values, and FCR was inversely associated with age, neuropathy, and high cryocrit levels. CONCLUSION: In patients with CV, HCV eradication may not correspond to a persistent clinical improvement, and clinical response may fluctuate. This implies an attentive approach to post-SVR evaluation through prognostic factors and tailored treatment.

Inflammation and Fibrogenesis in MAFLD: Role of the Hepatic Immune System.

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is the definition recently proposed to better circumscribe the spectrum of conditions long known as non-alcoholic fatty liver disease (NAFLD) that range from simple steatosis without inflammation to more advanced liver diseases. The progression of MAFLD, as well as other chronic liver diseases, toward cirrhosis, is driven by hepatic inflammation and fibrogenesis. The latter, result of a "chronic wound healing reaction," is a dynamic process, and the understanding of its underlying pathophysiological events has increased in recent years. Fibrosis progresses in a microenvironment where it takes part an interplay between fibrogenic cells and many other elements, including some cells of the immune system with an underexplored or still unclear role in liver diseases. Some therapeutic approaches, also acting on the immune system, have been probed over time to evaluate their ability to improve inflammation and fibrosis in NAFLD, but to date no drug has been approved to treat this condition. In this review, we will focus on the contribution of the liver immune system in the progression of NAFLD, and on therapies under study that aim to counter the immune substrate of the disease.

PNPLA3, TM6SF2, and MBOAT7 Influence on Nutraceutical Therapy Response for Non-alcoholic Fatty Liver Disease: A Randomized Controlled Trial.

Introduction: PNPLA3, TM6SF2, and MBOAT7 genes play a crucial role in non-alcoholic fatty liver disease (NAFLD) development and worsening. However, few data are available on their treatment response influence. The aim of this trial is to explore the effect derived from silybin-phospholipids complex (303 mg of silybin-phospholipids complex, 10 µg of vitamin D, and 15 mg of vitamin E twice a day for 6 months) oral administration in NAFLD patients carrying PNPLA3-rs738409, TM6SF2-rs58542926, or MBOAT7-rs641738 genetic variants. Materials and Methods: In all, 92 biopsy-proven NAFLD patients were grouped in 30 NAFLD wild type controls, 30 wild type treated patients, and 32 mutated treated ones. We assessed glycemia (FPG), insulinemia, HOMA-IR, aspartate and alanine aminotransferases (AST, ALT), C-reactive protein (CRP), thiobarbituric acid reactive substance (TBARS), stiffness, controlled attenuation parameter (CAP), dietary daily intake, and physical activity at baseline and end of treatment. Results: The wild-type treated group showed a significant improvement of FPG, insulinemia, HOMA-IR, ALT, CRP, and TBARS (p < 0.05), whereas no improvements were recorded in the other two study groups. NAFLD wild type treated patients showed higher possibilities of useful therapeutic outcome (p < 0.01), obtained from the prescribed therapeutic regimen, independently from age, sex, comorbidities, medications, CAP, and stiffness in comparison to the mutated group. Discussion: The assessed mutations are independently associated with no response to a silybin-based therapeutic regimen and could be considered as useful predictive markers in this context. Clinical Trial Registry Number: www.ClinicalTrials.gov, identifier: NCT04640324.

Viral hepatitis: Milestones, unresolved issues, and future goals.

In this review the current overall knowledge on hepatitis A, B, C, D, and E will be discussed. These diseases are all characterized by liver inflammation but have significant differences in distribution, transmission routes, and outcomes. Hepatitis B virus and hepatitis C virus are transmitted by exposure to infected blood, and in addition to acute infection, they can cause chronic hepatitis, which in turn can evolve into cirrhosis. It is estimated that more than 300 million people suffer from chronic hepatitis B or C worldwide. Hepatitis D virus, which is also transmitted by blood, only affects hepatitis B virus infected people, and this dual infection results in worse liver-related outcomes. Hepatitis A and E spread via the fecal-oral route, which corresponds mainly to the ingestion of food or water contaminated with infected stools. However, in developed countries hepatitis E is predominantly a zoonosis. Although hepatitis A virus and hepatitis E virus are usually responsible for a self-limiting hepatitis, a serious, rarely fatal illness is also possible, and in immunosuppressed patients, such as organ transplant recipients, hepatitis E virus infection can become chronic. The description of goals achieved, unresolved issues, and the latest research on this topic may make it possible to speculate on future scenarios in the world of viral hepatitis.

Corrigendum to "Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease".

[This corrects the article DOI: 10.1155/2018/9547613.].

Solving the Gap Between HCV Detection and Treatment in Prison HCVRNA Testing and Treatment in a Cohort of Newly Arrived Convicts in Southern Italy.

INTRODUCTION: HCV infection elimination is set to be carried out by 2030. To achieve this goal, the WHO has set minor achievable short-term "mini-goals." One of these is treating "difficult to reach and treat populations," such as prisoners. One of the biggest obstacles to achieving this mini goal is the poor knowledge of the real HCV prevalence in such a population and the barriers to its detection, treatment, and follow-up. Even if HCV testing in Italian prisons is feasible and recommended, it is not however always carried out. To worsen the picture, the peculiar status of conviction is correlated to difficulty in caring out the antiviral therapy due to loss in follow-up and to the refusals by inmates. AIMS: A point-of-care test-and-treat program was set up in a penitentiary in Southern Italy to reduce the number of patients Lost To Follow-Up (LTFU) between detection and treatment. A secondary aim was to evaluate the prevalence of HCV-infected patients in a cohort of newly arrived inmates. METHODS: This prospective-observational study was carried out from January 2020 to February 2020. We performed an HCV-RNA blood capillary quick test on all newly arrived inmates. As a routine, the new inmates underwent clinical and laboratory assessments. To those who were detected HCV-RNA positive, the shortest possible antiviral treatment was offered, according to genotype and clinical features. RESULTS: We observed 122 new inmates in the period between January and February of 2020. Overall, 62 (50.8%) subjects took HCV-RNA quick testing through blood sampling. Four (6.4%) subjects were found to be HCV-RNA positive; 1 refused antiviral therapy, while 3 accepted, obtaining 100% SVR. None of the HCV-active inmates were lost to follow up between detection and treatment proposal. CONCLUSION: The use of a high-speed test-and-treat protocol for HCV infection was demonstrated to be effective in avoiding LTFU in HCV-positive new inmates in the period between detection and treatment. We observed an apparent prevalence of HCV incident cases in newly arrived inmates of 6.4%. Antiviral therapy was quickly provided and found to be effective and successful.

Nutrigenomics and Nutrigenetics in Metabolic- (Dysfunction) Associated Fatty Liver Disease: Novel Insights and Future Perspectives.

Metabolic- (dysfunction) associated fatty liver disease (MAFLD) represents the predominant hepatopathy and one of the most important systemic, metabolic-related disorders all over the world associated with severe medical and socio-economic repercussions due to its growing prevalence, clinical course (steatohepatitis and/or hepatocellular-carcinoma), and related extra-hepatic comorbidities. To date, no specific medications for the treatment of this condition exist, and the most valid recommendation for patients remains lifestyle change. MAFLD has been associated with metabolic syndrome; its development and progression are widely influenced by the interplay between genetic, environmental, and nutritional factors. Nutrigenetics and nutrigenomics findings suggest nutrition's capability, by acting on the individual genetic background and modifying the specific epigenetic expression as well, to influence patients' clinical outcome. Besides, immunity response is emerging as pivotal in this multifactorial scenario, suggesting the interaction between diet, genetics, and immunity as another tangled network that needs to be explored. The present review describes the genetic background contribution to MAFLD onset and worsening, its possibility to be influenced by nutritional habits, and the interplay between nutrients and immunity as one of the most promising research fields of the future in this context.

Characterisation of asymptomatic patients and efficacy of preventive measures for SARS-CoV-2 infection in a large population of Southern Italy: a cohort study.

BACKGROUND: The SARS-CoV-2 pandemic has infected millions of people and has caused more than 2.30 million deaths worldwide to date. Several doubts arise about the role of asymptomatic carriers in virus transmission. During the first epidemic outbreak in Italy a large screening with nasopharyngeal swab (NS) was performed in those who were considered 'suspect' for infection. AIMS: To report the results of the SARS-CoV-2 screening in a province in Southern Italy and to provide data on the COVID-19 epidemic and the burden of asymptomatic subjects. PATIENTS AND METHODS: A retrospective cohort study was set up in all healthcare facilities of the province (12 hospitals and 13 sanitary districts: primary, secondary and tertiary centres) with the aim to analyse the results of NS performed on all subjects suspected to be infected with SARS-CoV-2, either because they presented symptoms suggestive of SARS-CoV-2 infection, they were 'contacts' of positive subjects, they came from areas with high prevalence or they were healthcare workers. NS were performed and managed as indicated by international guidelines. The specimens were processed for SARS-CoV-2 detection by real-time PCR. RESULTS: A total of 20 325 NS were performed from 13 March to 9 May 2020. Of these, 638 (3.14%) were positive. 470 were asymptomatic, or 75.3% of persons who were positive. They were mostly among 'contacts' of symptomatic cases (428 of 470, 91%) and were in domiciliary isolation. Expression of three SARS-CoV-2 genes did not differ between asymptomatic and symptomatic subjects. The strict measures with regard to social distancing led to a continuous decrease in cases during phase 1. CONCLUSIONS: In a large area in Southern Italy, 3.14% (638 of 20 325) of the total subjects tested were positive for SARS-CoV-2. Most of them were asymptomatic (470 of 624, 75.3%), and of these 91% (428 of 470) were 'close contacts' of symptomatic subjects. The combination of social distancing together with the systematic screening of close contacts of COVID-19-positive symptomatic subjects seems to be an efficacious approach to limit the spread of the epidemic.