Acoustic Radiation Forced Impulse of the Liver and the Spleen, Combined with Spleen Dimension and Platelet Count in New Ratio Scores, Identifies High-Risk Esophageal Varices in Well-Compensated Cirrhotic Patients.

Acoustic radiation forced impulse (ARFI) is an integrated ultrasound method, measuring stiffness by point shear wave elastography. To evaluate the diagnostic performance of the ARFI of the liver and the spleen, combined with spleen dimension and platelet count, in predicting high-risk esophageal varices (HRVs) in cirrhotic patients, a prospective and cross-sectional study was conducted between February 2017 and February 2021. The following ratio scores were calculated based on ARFI measurements: ALSDP (ARFI Liver-Spleen Diameter-to-Platelet Ratio Score), ASSDP (ARFI Spleen-Spleen Diameter-to-Platelet Ratio Score), ASSAP (ARFI Spleen-Spleen Area-to-Platelet Ratio Score), and ALSAP (ARFI Liver-Spleen Area-to-Platelet Ratio Score). In 100 enrolled subjects, spleen ARFI, ASSDP, and ASSAP were significantly associated with HRVs in the prospective short- and long-term follow-ups and in the cross-sectional study (p < 0.05), while ALSDP and ALSAP were associated with HRVs only in the prospective long-term follow-up and cross-sectional study (p< 0.05). ASSAP was the best ARFI ratio score for HRVs at the long-term follow-up [value of area under curve (AUC) = 0.88], although all the ARFI ratio scores performed better than individual liver and spleen ARFI (AUC > 0.7). In our study, ARFI ratio scores can predict, in well-compensated cirrhotic patients, the risk of developing HVRs in short- and long-term periods.

Approaching the Sarcopenic Patient with Nonalcoholic Steatohepatitis-related Cirrhosis.

Sarcopenia is a well-known complication of chronic liver disease (CLD), and it is almost always observed in patients with cirrhosis, at least in those with decompensated disease. Since nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is becoming the leading cause of end-stage liver disease, a new scenario characterized by the frequent coexistence of NAFLD, obesity, and sarcopenia is emerging. Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants, it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes. Notably, during the course of CLD, deregulation of the liver-muscle-adipose tissue axis has been described. Unfortunately, owing to the lack of properly designed studies, specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined. Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate. This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise. Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.

Non-invasive assessment of hepatic steatosis by ultrasound-derived fat fraction in individuals at high-risk for metabolic dysfunction-associated steatotic liver disease.

AIMS: Given the increasing number of individuals developing metabolic dysfunction-associated steatotic liver disease (MASLD) and the low rate of those with progressive liver disease, there is a pressing need to conceive affordable biomarkers to assess MASLD in general population settings. Herein, we aimed to investigate the performance of the ultrasound-derived fat fraction (UDFF) for hepatic steatosis in high-risk individuals. METHODS: A total of 302 Europeans with obesity, type 2 diabetes, or a clinical history of hepatic steatosis were included in the analyses. Clinical, laboratory, and imaging data were collected using standardized procedures during a single screening visit in Rome, Italy. Hepatic steatosis was defined by controlled attenuation parameter (CAP) or ultrasound-based Hamaguchi's score. UDFF performance for hepatic steatosis was estimated by the area under the receiver operating characteristic curve (AUC). RESULTS: Overall, median (IQR) UDFF was 12% (7-20). UDFF was positively correlated with CAP (ρ = 0.73, p < 0.0001) and Hamaguchi's score (ρ = 0.79, p < 0.0001). Independent predictors of UDFF were circulating triglycerides, alanine aminotransferase (ALT), and ultrasound-measured visceral adipose tissue (VAT). UDFF AUC was 0.89 (0.85-0.93) and 0.92 (0.88-0.95) for CAP- and ultrasound-diagnosed hepatic steatosis, respectively. UDFF AUC for hepatic steatosis was higher than those of fatty liver index (FLI), hepatic steatosis index (HSI), CAP-score (CAPS), and ALT (p < 0.0001). Lower age, ALT, and VAT were associated with discordance between UDFF and ultrasound. CONCLUSIONS: UDFF may be a simple and accurate imaging biomarker to assess hepatic steatosis and monitor changes in hepatic fat content over time or in response to therapeutic interventions beyond clinical trials.

Prognostication in NAFLD: physiological bases, clinical indicators, and newer biomarkers

Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic in Western countries. Notably, while the majority of NAFLD patients will not evolve until advanced liver disease, a minority of them will progress towards liver-related events. Therefore, risk stratification and prognostication are emerging as fundamental in order to optimize human and economic resources for the care of these patients. Liver fibrosis has been clearly recognized as the main predictor of poor hepatic and extrahepatic outcomes. However, a prediction based only on the stage of fibrosis is near-sighted and static, as it does not capture the propensity of disease to further progress, the speed of progression and their changes over time. These determinants, which result from the interaction between genetic predisposition and acquired risk factors (obesity, diabetes, etc.), express themselves in disease activity, and can be synthesized by biomarkers of hepatic inflammation and fibrogenesis. In this review, we present the currently available clinical tools for risk stratification and prognostication in NAFLD specifically with respect to the risk of progression towards hard hepatic outcomes, i.e., liver-related events and death. We also discuss about the genetic and acquired drivers of disease progression, together with the physiopathological bases of their come into action. Finally, we introduce the most promising biomarkers in the direction of repeatedly assessing disease activity over time, mainly in response to future therapeutic interventions. (AU)

Prognostication in NAFLD: physiological bases, clinical indicators, and newer biomarkers.

Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic in Western countries. Notably, while the majority of NAFLD patients will not evolve until advanced liver disease, a minority of them will progress towards liver-related events. Therefore, risk stratification and prognostication are emerging as fundamental in order to optimize human and economic resources for the care of these patients.Liver fibrosis has been clearly recognized as the main predictor of poor hepatic and extrahepatic outcomes. However, a prediction based only on the stage of fibrosis is near-sighted and static, as it does not capture the propensity of disease to further progress, the speed of progression and their changes over time. These determinants, which result from the interaction between genetic predisposition and acquired risk factors (obesity, diabetes, etc.), express themselves in disease activity, and can be synthesized by biomarkers of hepatic inflammation and fibrogenesis.In this review, we present the currently available clinical tools for risk stratification and prognostication in NAFLD specifically with respect to the risk of progression towards hard hepatic outcomes, i.e., liver-related events and death. We also discuss about the genetic and acquired drivers of disease progression, together with the physiopathological bases of their come into action. Finally, we introduce the most promising biomarkers in the direction of repeatedly assessing disease activity over time, mainly in response to future therapeutic interventions.

Development and Validation of a Score for Fibrotic Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Noninvasive assessment of histological features of nonalcoholic fatty liver disease (NAFLD) has been an intensive research area over the last decade. Herein, we aimed to develop a simple noninvasive score using routine laboratory tests to identify, among individuals at high risk for NAFLD, those with fibrotic nonalcoholic steatohepatitis (NASH) defined as NASH, NAFLD activity score ≥4, and fibrosis stage ≥2. METHODS: The derivation cohort included 264 morbidly obese individuals undergoing intraoperative liver biopsy in Rome, Italy. The best predictive model was developed and internally validated using a bootstrapping stepwise logistic regression analysis (2000 bootstrap samples). Performance was estimated by the area under the receiver operating characteristic curve (AUROC). External validation was assessed in 3 independent European cohorts (Finland, n = 370; Italy, n = 947; England, n = 5368) of individuals at high risk for NAFLD. RESULTS: The final predictive model, designated as Fibrotic NASH Index (FNI), combined aspartate aminotransferase, high-density lipoprotein cholesterol, and hemoglobin A1c. The performance of FNI for fibrotic NASH was satisfactory in both derivation and external validation cohorts (AUROC = 0.78 and AUROC = 0.80-0.95, respectively). In the derivation cohort, rule-out and rule-in cutoffs were 0.10 for sensitivity ≥0.89 (negative predictive value, 0.93) and 0.33 for specificity ≥0.90 (positive predictive value, 0.57), respectively. In the external validation cohorts, sensitivity ranged from 0.87 to 1 (negative predictive value, 0.99-1) and specificity from 0.73 to 0.94 (positive predictive value, 0.12-0.49) for rule-out and rule-in cutoff, respectively. CONCLUSION: FNI is an accurate, simple, and affordable noninvasive score which can be used to screen for fibrotic NASH in individuals with dysmetabolism in primary health care.

Thrombocytopenia in chronic liver disease: Physiopathology and new therapeutic strategies before invasive procedures.

Chronic liver disease is characterized by several hematological derangements resulting in a complex and barely rebalanced haemostatic environment. Thrombocytopenia is the most common abnormality observed in these patients and recent advances have led to researchers focus the attention on the multifactorial origin of thrombocytopenia and on the key role of thrombopoietin (TPO) in its physiopathology. Severe thrombocytopenia (platelet count < 50000/µL) complicates the management of patients with chronic liver disease by increasing the potential risk of bleeding for invasive procedures, which may be therefore delayed or canceled even if lifesaving. In the very last years, the development of new drugs which exceed the limits of the current standard of care (platelet transfusions, either immediately before or during the procedure) paves the way to a new scenario in the management of this population of patients. Novel agents, such as the TPO-receptor agonists avatrombopag and lusutrombopag, have been developed in order to increase platelet production as an alternative to platelet transfusions. These agents have demonstrated a good profile in terms of efficacy and safety and will hopefully allow reducing limitations and risks associated with platelet transfusion, without any delay in scheduled interventions. Altogether, it is expected that patients with chronic liver disease will be able to face invasive procedures with one more string in their bow.

Sarcopenia in Hepatocellular Carcinoma: Pathogenesis and Management.

BACKGROUND: Sarcopenia is almost constantly observed in patients with cirrhosis and hepatocellular carcinoma (HCC). SUMMARY: Chronic liver disease represents a unique pathophysiological scenario in which sarcopenia develops and all factors involved in the pathogenesis should be taken into account for an appropriate management of the disease. No properly designed intervention studies on this topic are available and, thus, no effective strategies have been developed for clinical practice. Apart from any targeted intervention, treatment, and optimization of liver disease is crucial. KEY MESSAGES: In patients with cirrhosis and HCC, nutritional support to maintain and restore nutrition status, a targeted use of branched-chain amino acids and a guided physical exercise, should all be an integral part of the multidimensional assessment and tailored interventions.

A Polygenic Risk Score to Refine Risk Stratification and Prediction for Severe Liver Disease by Clinical Fibrosis Scores.

BACKGROUND & AIMS: A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content [PRS-HFC]). Here, we hypothesized that the addition of PRS-HFC to clinical fibrosis scores may improve risk stratification and prediction of severe liver disease (SLD). METHODS: We used data from 266,687 individuals in the UK Biobank, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation during a median follow-up period of 9 years. Nonalcoholic fatty liver disease fibrosis score, Fibrosis-4, aspartate aminotransferase-to-platelet ratio, BARD, and Forns scores, and PRS-HFC, were computed. All analyses were stratified according to the presence of diabetes, obesity, and a positive fatty liver index (≥60). RESULTS: Unfavorable genetics (PRS-HFC, ≥0.396) further stratified the risk of SLD in subjects in intermediate-/high-risk classes of fibrosis scores, with a higher effect in those with metabolic risk factors, and the prediction was improved by integrating PRS-HFC (areas under the receiver operating characteristic increased for all scores with a P value of approximately 10-2 to 10-4, except for the aspartate aminotransferase-to-platelet ratio in the overall population and in subjects with obesity). PRS-HFC improved diagnostic accuracies and positive predictive values for SLD in intermediate-high clinical score risk classes. Risk stratification and prediction were not affected or were poorly affected by unfavorable genetics in subjects without metabolic risk factors. CONCLUSIONS: Integration of genetics with clinical fibrosis scores refines individual risk and prediction for SLD, mainly in individuals at risk for nonalcoholic fatty liver disease. These data provide evidence from a prospective cohort that common genetic variants capture additional prognostic insights not conveyed by validated clinical/biochemical parameters.

Metabolic and genetic determinants for progression to severe liver disease in subjects with obesity from the UK Biobank.

BACKGROUND: Obesity is among the main determinants of nonalcoholic fatty liver disease progression towards severe liver disease (SLD). However, risk factors for SLD in individuals with obesity have not been examined. OBJECTIVES: To identify the independent risk factors for SLD among participants with obesity from the UK Biobank. METHODS: A total of 80,224 UK Biobank participants with obesity (body mass index[BMI] > 30 kg/m2) and 242,822 without obesity, of European descent without clinical history of liver disease and liver cancer were prospectively followed for the onset of SLD, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma and/or liver transplantation. Risk factors for incident SLD were assessed by Cox proportional hazards models. Different clinical phenotypes were derived by latent class analysis (LCA). RESULTS: Obesity conferred a 2.6-fold increased risk for SLD that was abolished after the inclusion of waist circumference (WC) in the model. Among individuals with obesity, age (adjusted hazard ratio [aHR] 1.05, 95%CI 1.03-1.07, p = 3.9 * 10-7), type 2 diabetes (aHR 2.18, 95%CI 1.55-3.05, p = 6.2 * 10-6), PNPLA3 rs738409 (aHR 1.59, 95%CI 1.33-1.9, p = 3.1 * 10-7) and WC (aHR 1.04, 95%CI 1.02-1.06, p = 8.5 * 10-6) were independent predictors of SLD. BMI category-specific WC thresholds allowed a better risk stratification compared to traditional ones. By LCA, the clinical phenotype at highest risk for SLD was that with BMI < 35 kg/m2 and WC above BMI-category specific thresholds. CONCLUSIONS: Age, WC, type 2 diabetes, and the PNPLA3 variant are the main risk factors for SLD in individuals with obesity. WC is the principal mediator of SLD risk conveyed by increased BMI. BMI category-specific WC-thresholds may refine the SLD risk more accurately than traditional thresholds.

Accuracy of controlled attenuation parameter for assessing liver steatosis in individuals with morbid obesity before bariatric surgery.

BACKGROUND & AIMS: The ultrasound-based controlled attenuation parameter (CAP) is a non-invasive tool widely validated for assessing liver steatosis across different etiologies. However, few studies, with liver biopsy available, have investigated its performance in individuals with morbid obesity. Herein, we aimed to evaluate the diagnostic accuracy of CAP in participants with morbid obesity from the MAFALDA study before bariatric surgery. METHODS: A total of 120 individuals with valid examinations within three months from bariatric surgery were included. Clinical, laboratory, FibroScan® (XL probe), and liver biopsy data were collected using standardized procedures. The overall accuracy of CAP for detecting liver steatosis was estimated by the area under the receiver-operating characteristics curve (AUROC). Optimal cut-offs were chosen at points with the highest Youden index. RESULTS: The AUROCs of CAP for detecting S ≥ S1, S ≥ S2, and S = S3 were 0.91 (95% CI 0.86-0.97), 0.83 (95% CI 0.76-0.90), and 0.86 (95% CI 0.79-0.94), respectively. The best CAP cut-offs for S ≥ S1, S ≥ S2, and S = S3 were 300 dB/m (95% CI 275-316), 328 dB/m (95% CI 296-345), and 344 dB/m (95% CI 343-352), respectively. CAP values were independently influenced by steatosis grade (estimate 20.60, 95% CI 12.70-28.40, P = 1.05 × 10-6 ). The AUROC of FibroScan-AST (FAST) score for detecting progressive non-alcoholic steatohepatitis was 0.76 (95% CI 0.66-0.86). CONCLUSIONS: In individuals with morbid obesity, CAP measured by XL probe is an accurate non-invasive tool for grading liver steatosis. Measurement of liver fat content by CAP may help identify those eligible for bariatric procedures and estimate the effect of bariatric surgery on hepatic steatosis. LAY SUMMARY: The ultrasound-based controlled attenuation parameter (CAP) by using the XL probe has an excellent performance for grading liver steatosis among individuals with morbid obesity. CAP may represent an accurate tool for the non-invasive assessment of liver steatosis among individuals with morbid obesity before and after bariatric surgery.

Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver.

Recent studies demonstrated reduced blood lysosomal acid lipase (LAL) activity in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to verify hepatic LAL protein content and activity in in vitro and in vivo models of fat overload and in NAFLD patients. LAL protein content and activity were firstly evaluated in Huh7 cells exposed to high-glucose/high-lipid (HGHL) medium and in the liver of C57BL/6 mice fed with high-fat diet (HFD) for 4 and 8 months. LAL protein was also evaluated by immunohistochemistry in liver biopsies from 87 NAFLD patients and 10 controls, and correlated with hepatic histology. Huh7 cells treated with HGHL medium showed a significant reduction of LAL activity, which was consistent with reduced LAL protein levels by western blotting using an antibody towards the N-term of the enzyme. Conversely, antibodies towards the C-term of the enzyme evidenced LAL accumulation, suggesting a post-translational modification that masks the LAL N-term epitope and affects enzymatic activity. Indeed, we found a high rate of ubiquitination and extra-lysosomal localization of LAL protein in cells treated with HGHL medium. Consistent with these findings, inhibition of proteasome triggered dysfunctional LAL accumulation and affected LAL activity. Accumulation of ubiquitinated/dysfunctional LAL was also found in the liver of HFD fed mice. In NAFLD patients, hepatic levels of non-ubiquitinated/functional LAL were lower than in controls and inversely correlated with disease activity and some of the hallmarks of reduced LAL. Fat overload leads to LAL ubiquitination and impairs its function, possibly reducing hepatic fat disposal and promoting NAFLD activity.

Combined evaluation of aminotransferases improves risk stratification for overall and cause-specific mortality in older patients.

BACKGROUND: Recent studies identified low levels of alanine aminotransferase (ALT) as strong predictors of mortality in older people. AIMS: Here we verified if the combined evaluation of aminotransferases may improve risk stratification for adverse outcomes in older patients. METHODS: Data are from 761 participants aged more than 65 years from a prospective population-based database (InCHIANTI study), without known baseline chronic liver disease or malignancies. Associations between aminotransferase levels and the risk of all-cause, cardiovascular- and cancer-death were assessed by Cox-models with time-dependent covariates. RESULTS: The association of ALT and aspartate aminotransferase (AST) with mortality was non-linear, mirroring a J- and a U-shaped curve, respectively. Based on quintiles of transaminase activities and on their association with overall mortality, low, intermediate (reference group) and high levels were defined. Having at least one transaminase in the low range [aHR 1.76 (1.31-2.36), p < 0.001], mainly if both [(aHR 2.39 (1.81-3.15), p < 0.001], increased the risk of overall mortality, as well as having both enzymes in the high range [aHR 2.14 (1.46-3.15), p < 0.001]. While similar trends were confirmed with respect to cardiovascular mortality, subjects with the highest risk of cancer mortality were those with both enzymes in the high range [aHR 3.48 (1.43-8.44), p = 0.006]. Low levels of transaminases were associated with frailty, sarcopenia and disability, while high levels did not capture any known proxy of adverse outcome. Conclusions and discussion The prognostic information is maximized by the combination of the 2 liver enzymes. While both aminotransferases in low range are characteristically found in the most fragile phenotype, both enzymes in high range are more likely to identify new-onset vascular/infiltrative diseases with adverse outcome.

Inborn and acquired risk factors for severe liver disease in Europeans with type 2 diabetes from the UK Biobank.

BACKGROUND & AIMS: Type 2 diabetes is a major driver of fatty liver disease and its long-term complications. The aim of this study was to investigate the individual contribution of inborn and acquired risk factors for severe liver disease in individuals with type 2 diabetes from the UK Biobank study. METHODS: A total of 22,812 UK Biobank participants of European descent without clinical history of liver disease and liver cancer were prospectively followed for the development of severe liver disease, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation from the National Health Service records. The contribution of inborn and acquired risk factors to the risk of incident severe liver disease was assessed by Cox proportional hazards models. RESULTS: During a median follow-up of 8.9 years (IQR 8.1-9.6), there were 279 individuals with severe liver disease, including 255 with cirrhosis and/or decompensated liver disease, 47 with hepatocellular carcinoma, and 5 with liver transplantation; death from severe liver disease occurred in 83 individuals. Risk factors independently associated with increased risk of incident severe liver disease included abnormal aspartate aminotransferase (adjusted hazard ratio [aHR] 4.85, 95% CI 2.76-8.54), decrease in serum albumin (aHR 2.39, 95% CI 1.76-3.24) and platelet count (aHR 1.12, 95% CI 1.09-1.16), cardiovascular disease (aHR 1.86, 95% CI 1.23-2.79), microalbuminuria (aHR 1.55, 95% CI 1.04-2.30), PNPLA3 rs738409 (aHR 1.67, 95% CI 1.27-2.18) and TM6SF2 rs58542926 (aHR 1.63, 95% CI 1.12-2.39), while the net effect of male sex was protective (aHR 0.49, 95% CI 0.26-0.94). CONCLUSIONS: These findings may help in clinical care to identify individuals with type 2 diabetes at risk of severe liver disease, in turn leading to personalised risk prediction and prevention strategies. LAY SUMMARY: Type 2 diabetes is a key driver of severe liver disease, namely cirrhosis, hepatocellular carcinoma, and liver-related mortality. In Europeans with type 2 diabetes from the prospective UK Biobank study, abnormal liver function, cardiovascular disease, microalbuminuria, and genetic variants in PNPLA3 and TM6SF2 genes are the major independent risk factors for severe liver disease. These findings may contribute in clinical care to identify and closely monitor individuals with type 2 diabetes at risk of developing severe liver disease, requiring more intensive follow-up strategies.

Steroid-refractory immune related hepatitis may hide viral re-activation.

Cancer immunotherapy has become a stronghold in modern oncology. Immune checkpoint inhibitors, in particular anti-PD-1 and anti-PD-L1 antibodies, are approved for the treatment of several solid cancers. In the near future, an increasing number of patients will be eligible for immunotherapy. Therefore, the management of immune-related adverse events is a daily challenge in clinical practice, among which hepatic immune-related toxicity has been described as a rare adverse event. We report the case of a patient treated with nivolumab (an anti-PD-L1 antibody) for a stage IV resected melanoma who developed recurrence of steroid-refractory liver toxicity that was later discovered to be associated with acute exacerbation of chronic undiagnosed hepatitis B. The patient significantly benefited from antiviral treatment. We conclude that serological viral screening is strongly recommended before starting immune checkpoint inhibitor treatment.

The PNPLA3 rs738409 variant can increase the risk of liver toxicity in multiple sclerosis patients treated with beta-interferon.

BACKGROUND: Liver toxicity can limit the use of interferon-beta (IFNß), a well-established treatment for multiple sclerosis (MS). Unfortunately, known risk-factors for IFNß-associated liver toxicity are few and of limited clinical utility. Susceptibility to drug-induced toxicity is influenced by genetic factors affecting hepatic lipid metabolism and drug-metabolizing activity. METHODS: We designed a retrospective, multicentre study to evaluate whether specific polymorphisms in genes involved in hepatic lipid metabolism are associated with a higher risk of developing IFNß-induced hepatotoxicity. The following single nucleotide polymorphisms were examined: rs738409 C > G in PNPLA3; rs4880 C > T in SOD2; rs3750861 C > T in KLF6; rs13412852 C > T in LPIN1; rs58542926 C > T in TM6SF2. Liver toxicity was defined as a new increase of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) plasma levels above the laboratory upper normal limit after the start of IFNß treatment. RESULTS: One-hundred-thirteen MS patients were enrolled and twenty-nine experienced liver toxicity. Logistic regression analysis revealed that the PNPLA3 variant was significantly associated with the occurrence of liver toxicity. No associations were found between other polymorphisms and liver toxicity. CONCLUSIONS: The results of our exploratory study suggest that the PNPLA3 variant can help to identify those patients at higher risk of IFNß toxicity. The stratification of the risk of liver toxicity could increase the safety of IFNß therapy.

Current Treatment Options for HCC: From Pharmacokinetics to Efficacy and Adverse Events in Liver Cirrhosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the world's most common cancers. For over ten years, the only medical treatment for it has been the multikinase inhibitor Sorafenib. Currently, however, other first or second-line therapeutic options have also shown efficacy against HCC, such as multikinase inhibitors (Regorafenib, Lenvatinib, and Cabozantinib), a monoclonal antibody against the vascular endothelial growth factor receptor 2 (Ramucirumab), and immune-checkpoint inhibitors (Nivolumab, Pembrolizumab, Ipilimumab). AIM: The aim of this paper is to review the metabolic pathways of drugs that have been tested for the treatment of HCC and the potential influence of liver failure over those pathways. METHODS: The Food and Drug Administration (FDA)'s and European Medicines Agency (EMA)'s datasheets, results from clinical trials and observational studies have been reviewed. RESULTS: This review summarizes the current knowledge regarding targets, metabolic pathways, drug interactions, and adverse events of medical treatments for HCC in cirrhotic patients. CONCLUSION: The new scenario of systemic HCC therapy includes more active drugs with different metabolic pathways and different liver adverse events. Clinical and pharmacological studies providing more data on the safety of these molecules are urgently needed.

Lipophagy Impairment Is Associated With Disease Progression in NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is associated with aging and features of metabolic syndrome. Lipotoxicity and oxidative stress are consequent to dysregulation of lipid metabolism and lipid accumulation, leading to hepatocyte injury and inflammation. Lipophagy consists in selective degradation of intracellular lipid droplets by lysosome and mounting evidence suggests that lipophagy is dysregulated in NAFLD. Here we demonstrate lipophagy impairment in experimental models of NAFLD and in a NAFLD patient cohort by histomorphological and molecular analysis. High fat diet-fed C57BL/6J male mice and high-fat/high-glucose cultured Huh7 cells showed accumulation of both p62/SQSTM1 and LC3-II protein. In 59 NAFLD patients, lipid droplet-loaded lysosomes/lipolysosomes and p62/SQSTM1 clusters correlated with NAFLD activity score (NAS) and with NAS and fibrosis stage, respectively, and levels of expression of lysosomal genes, as well as autophagy-related genes, correlated with NAS and fibrosis stage. An increased amount of lipid droplets, lipolysosomes and autophagosomes was found in subjects with NAFLD compared to healthy subjects at ultrastructural level. In conclusion, here we observed that NAFLD is characterized by histological, ultrastructural and molecular features of altered autophagy that is associated with an impaired lipid degradation. Impaired autophagy is associated with features of advanced disease. Lipopolysosomes, as individuated with light microscopy, should be further assessed as markers of disease severity in NAFLD patients.