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The potential benefits of adopting Metabolic dysfunction-associated steatotic liver disease (MASLD) rather than Metabolic dysfunction-associated fatty liver disease (MAFLD) diagnostic criteria in defining the disease progression risk of steatotic (SLD) patients have never been prospectively evaluated. To compare MASLD and MAFLD criteria in estimating the 5-year risk of advanced chronic liver disease (ACLD) progression and hepatocellular carcinoma (HCC) occurrence in lean (L) and not-lean (NL) SLD patients. Between January 2014 and June 2019, 931 ultrasonographic-defined-SLD patients were recruited, excluding individuals with ACLD, alcoholism, and other causes of steatosis. Baseline biochemical and clinical data were collected, including Liver Stiffness (LSM) (>9.7 kPa= advanced fibrosis-AF; >15 kPa=ACLD) and Controlled-Attenuation-Parameter (CAP) (>293-db/m=Severe-steatosis-S3). Patients were observed annually or semiannually (AF) over 5 years, reassessing LSM, CAP, and HCC occurrence. In July 2024, based on baseline features, patients were a posteriori subdivided into "L" (Body-Mass-Index<25 kg/m2) (n.134) and "NL" (n.797) and, subsequently, by separately applying MAFLD and MASLD criteria, in L-MASLD (n.18), L-MASLD/MAFLD (n.82), L-MAFLD (n.34) and NL-MASLD (n.60), NL-MASLD/MAFLD (n.581), NL-MAFLD (n.156). At baseline, no differences in S3 (L, p :0.163; NL, p :0.103) and AF (L, p :0.718; NL, p :0.277) prevalences emerged. A higher 5-year ACLD progression (RR: 1.83, C.I.95%:1.357-2.431, p :0.0002) and HCC occurrence (RR:1.32, C.I.95%:1.032-1.451, p :0.03) risk was reported in NL-MASLD. Contrariwise, L-MAFLD presented a higher risk of ACLD progression (RR:2.11, C.I.95%: 1.171-2.250, p :0.01) and, even not significant, HCC occurrence (RR:1.588, C.I.95%:0.747-2.781, p :0.371). ACLD progression occurred in 33.34% L-MASLD vs 70.59% L-MAFLD (median: 43 vs 45.50 months; p: 0.0091).Logistic regression (adjusted for sex, age, diabetes, steatosis, and fibrosis severity) revealed high-sensitivity-C-reactive protein (aOR: 1.21; C.I. 95%: 1.052-2.183; p :0.02) and Homeostatic-model-assessment-for-insulin-resistance(aOR: 1.38; C.I. 95%: 1.151-2.275; p :0.01) as variables significantly associated with ACLD-progression in L-MAFLD. MASLD criteria better estimate the liver disease progression risk limitedly to SLD-NL patients. [ABSTRACT FROM AUTHOR]

Lifestyle modifications represent the main therapeutic intervention for Metabolic dysfunction-associated Steatotic Liver disease (MASLD). Unfortunately, the dietary-behavioral prescription is constantly limited by poor compliance. In this context, the benefits of motivational support remain unexplored. To evaluate the effectiveness of a multidisciplinary (hepatologist-nutritionist-psychologist) management in improving clinical outcomes in MASLD, via ameliorating adherence to specialistic tailored-indications. MASLD patients (n.286) were consecutively enrolled and randomized in three cohorts: 72 followed generic hepatologist-provided dietary advice ("H"), 71 also received a nutritionists-prescribed individualized intervention ("HN") (H+N= "standard of care"), and 143 were treated with an approach additionally involving cognitive/behavioral-based psychological support ("HNP") ("experimental-group"). At baseline, anthropometric, biochemical, clinical, liver stiffness (LSM), controlled attenuation parameter (CAP), lifestyle habits, and body composition values were recorded. Along 18 months, semestral hepatological (for all), nutritional (H and HN), and psychological (HNP) follow-ups reassessed parameters and evaluated compliance. After 18 months, the prevalence of patients achieving a ≥ 10% decrease in body weight was significantly higher in HNP (HNP:62.09%; HN:44.9%; H:35.8%; HNP vs HN, p :0.01; HNP vs H, p :0.0002). In HNP, a significant improvement in Homeostatic-model-assessment-for-insulin-resistance (p :0.001), HDL (p <0.0001), LSM (p :0.007), CAP (p :0.002), and Fat-Mass (p < 0.0001) was observed. Loss of compliance rate was significantly lower in HNP (HNP:12.08%; HN:34.7%; H:45.8%; HNP vs HN, HNP vs H, p :0.001). Relevantly, HNP patients presented a significantly lower risk of acute cardiovascular events (ACEs) during the observation period [HR: 0.497, IC (0.236-0.751) 95%, p :0.04)] (Figure). Logistic regression analysis (adjusted for sex, age, and cardiovascular risk factors) revealed HNP adherence as significantly associated with lower ACEs occurrence (aOR: 0.81; C.I. 95%: 0.55-0.97; p:0.02). Dynamic work, city life, and large family emerged as social factors influencing compliance (OR: 2.11, 1.78, 1.12) (all p <0.05). Integrating standard hepatological-nutritional with psychological support significantly improves the outcomes of MASLD patients. [ABSTRACT FROM AUTHOR]

The platelet (PLT) count is paramount in almost all the available non-invasive tools (NITs) predicting the first hepatic decompensation (FHD) in advanced chronic liver disease (ACLD). However, a non-negligible proportion of Metabolic dysfunction-associated Steatotic Liver Disease (MASLD)-related ACLD individuals presenting clinically significant portal hypertension (CSPH) do not show splenomegaly and hypersplenism-related thrombocytopenia. To evaluate the performance of NITs in predicting the 3-year FHD in CSPH-MASLD-cACLD, stratifying the study population according to the splenomegaly. Between 2018 and 2021, 148 splenic and 27 asplenic (25-splenectomized; 2-agenesis) nonselective-beta-blockers-(NSBB)-naïve MASLD-cACLD patients with endoscopic CSPH were enrolled. Patients subsequently received NSBBs and the response was surrogately evaluated following the available guidelines. Ultrasound AI-supported dedicated tools automatically defined spleen diameter and spleen area (SA), discriminating "Splenomegaly +" (91) and "Splenomegaly -" (57) patients. Patients were semiannually observed and the liver-related events were recorded. Albumin-bilirubin (ALBI) score and PLT count-incorporating NITs (PINs) [FIB-4, ALBI-FIB-4, red-cell-distribution-width/PLT-ratio, Liver-Stiffness-Measurement/PLT-ratio, and ANTICIPATE±NASH] were determined at baseline and during the follow-up. FHD occurred in 18.68% of "Splenomegaly+", 19.29% of "Splenomegaly-", and 22.22% of "Asplenic" individuals. The multivariate competing risk analysis (adjusted for sex, age, BMI, diabetes, MELD, and NSBB-response) revealed the PINs as modest predictors of FHD, highlighting SA as the variable more significantly associated with this outcome [aSHR: 0.870 (95% C.I.: 0.833-1.108), p <0.0001] in "Splenomegaly -", and ALBI [aSHR:1.273 (95% C.I.:1.199-1.305, p :0.002] as the only significantly predicting factors in the "Asplenic" group. Consistently, contrariwise to "Splenomegaly +", in "Splenomegaly -" and "Asplenic" individuals, ROC and time-dependent ROC analysis evidenced the poor performance of PINs in predicting HD at baseline, 1,1.5, and 2 years, evidencing only ALBI preserved a good accuracy (baseline AUC 0.651, p :0.04 and baseline AUC:0.625, p :0.03 respectively) (Figure). The spleen area dramatically affects the predictive performance of the PINs in CSPH-MASLD-cACLD patients. [ABSTRACT FROM AUTHOR]

1. The potent, functional agonist of the bile acid Takeda G-protein-coupled receptor 5 (TGR5), (S)-1-(6-fluoro- 2-methyl-3,4-dihydroquinolin-1(2H)-yl)-2-(isoquinolin-5-yloxy)ethanone (3), represents a useful tool to probe in vivo TGR5 pharmacology. Rapid degradation of 3 in both rat and mouse plasma, however, hindered the conduct of in vivo pharmacokinetic/pharmacodynamic investigations (including plasma-free fraction (fu plasma) determination) in rodent models of pharmacology. Studies were therefore initiated to understand the biochemical basis for plasma instability so that appropriate methodology could be implemented in in vivo pharmacology studies to prevent the breakdown of 3. 2. Compound 3 underwent amide bond cleavage in both rat and mouse plasma with half-lives (T1/2) of 39 ± 7 and 9.9 ± 0.1 min. bis(p-nitrophenyl) phosphate (BNPP), a specific inhibitor of carboxylesterases, was found to inhibit hydrolytic cleavage in a time- and concentration-dependent manner, which suggested the involvement of carboxylesterases in the metabolism of 3. In contrast with the findings in rodents, 3 was resistant to hydrolytic cleavage in both dog and human plasma. 3. The instability of 3 was also observed in rat and mouse liver microsomes. β-Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-dependent metabolism of 3 occurred more rapidly (T1/2 approximately 2.22-6.4 min) compared with the metabolic component observed in the absence of the co-factor (T1/2 approximately 89-130 min). Oxidative metabolism dominated the NADPH-dependent decline of 3, whereas NADPH-independent metabolism of 3 proceeded via simple amide bond hydrolysis. 4. Compound 3 was highly bound (approximately 95%) to both dog and human plasmas. Rat and mouse plasma, pre-treated with BNPP to inhibit carboxylesterases activity, were used to determine the fu plasma of 3. A BNPP concentration of 500 μM was determined to be optimal for these studies. Higher BNPP concentrations (1000 μM) appeared to displace 3 from its plasma protein-binding sites in preclinical species and human. Under the conditions of carboxylesterases-inhibited rat and mouse plasma, the level of protein binding displayed by 3 was similar to those observed in dog and human. 5. In conclusion, a novel system has been devised to measure fu plasma for a plasma-labile compound. The BNPP methodology can be potentially applied to stabilize hydrolytic cleavage of structurally diverse carboxylesterase substrates in the plasma (and other tissue), thereby allowing the characterization of pharmacology studies on plasma-labile compounds if and when they emerge as hits in exploratory drug- discovery programmes. [ABSTRACT FROM AUTHOR]

UGT2B4 is a highly expressed drug-metabolizing enzyme in the liver contributing to the glucuronidation of several drugs. To enable quantitatively assessing UGT2B4 contribution toward metabolic clearance, a potent and selective UGT2B4 inhibitor that can be used for reaction phenotyping was sought. Initially, a canagliflozin-2'- O -glucuronyl transferase activity assay was developed in recombinant UGT2B4 and human liver microsomes (HLM) [±2% bovine serum albumin (BSA)]. Canagliflozin-2'- O -glucuronidation (C2OG) substrate concentration at half-maximal velocity value in recombinant UGT2B4 and HLM were similar. C2OG formation intrinsic clearance was five- to seven-fold higher in incubations containing 2% BSA, suggesting UGT2B4 susceptibility to the inhibitory unsaturated long-chain fatty acids released during the incubation. Monitoring for C2OG formation, 180 compounds were evaluated for UGT2B4 inhibition potency in the presence and absence of 2% BSA. Compounds that exhibited an apparent UGT2B4 IC 50 of < 1 μ M in HLM with 2% BSA were evaluated for inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B10, UGT2B15, and UGT2B17 catalytic activities to establish selectivity suitable for supporting UGT reaction phenotyping. In this study, clotrimazole was identified as a potent UGT2B4 inhibitor (HLM apparent IC 50 of 11 to 35 nM ± 2% BSA). Moreover, clotrimazole exhibited selectivity for UGT2B4 inhibition (>24-fold) over the other UGT enzymes evaluated. Additionally, during this study it was discovered that the previously described UGT2B7 inhibitors 16 α - and 16 β -phenyllongifolol also inhibit UGT2B4. Clotrimazole, a potent and selective UGT2B4 inhibitor, will prove essential during UGT reaction phenotyping. SIGNIFICANCE STATEMENT: To mechanistically evaluate drug interactions, it is essential to understand the contribution of individual enzymes to the metabolic clearance of a drug. The present study describes the development of a UGT2B4 activity assay that enabled the discovery of the highly selective and potent UGT2B4 inhibitor clotrimazole. Clotrimazole can be used in UGT reaction phenotyping studies to estimate fractional contribution of UGT2B4., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Brepocitinib is an oral once-daily Janus kinase 1 and Tyrosine kinase 2 selective inhibitor currently in development for the treatment of several autoimmune disorders. Mass balance and metabolic profiles were determined using accelerator mass spectrometry in six healthy male participants following a single oral 60 mg dose of 14 C-brepocitinib (∼300 nCi). The average mass balance recovery was 96.7% ± 6.3%, with the majority of dose (88.0% ± 8.0%) recovered in urine and 8.7% ± 2.1% of the dose recovered in feces. Absorption of brepocitinib was rapid, with maximal plasma concentrations of total radioactivity and brepocitinib achieved within 0.5 hours after dosing. Circulating radioactivity consisted primarily of brepocitinib (47.8%) and metabolite M1 (37.1%) derived from hydroxylation at the C5' position of the pyrazole ring. Fractional contributions to metabolism via cytochrome P450 enzymes were determined to be 0.77 for CYP3A4/5 and 0.14 for CYP1A2 based on phenotyping studies in human liver microsomes. However, additional clinical studies are required to understand the potential contribution of CYP1A1. Approximately 83% of the dose was eliminated as N-methylpyrazolyl oxidative metabolites, with 52.1% of the dose excreted as M1 alone. Notably, M1 was not observed as a circulating metabolite in earlier metabolic profiling of human plasma from a multiple ascending dose study with unlabeled brepocitinib. Mechanistic studies revealed that M1 was highly unstable in human plasma and phosphate buffer, undergoing chemical oxidation leading to loss of the 5-hydroxy-1-methylpyrazole moiety and formation of aminopyrimidine cleavage product M2. Time-dependent inhibition and trapping studies with M1 yielded insights into the mechanism of this unusual and unexpected instability. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of brepocitinib, a JAK1/TYK2 inhibitor for atopic dermatitis, in humans as well as characterization of clearance pathways and pharmacokinetics of brepocitinib and its metabolites., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: For compensated advanced chronic liver disease (cACLD) patients, the first decompensation represents a dramatically worsening prognostic event. Based on the first decompensation event (DE), the transition to decompensated advanced chronic liver disease (dACLD) can occur through two modalities referred to as acute decompensation (AD) and non-AD (NAD), respectively. Clinically Significant Portal Hypertension (CSPH) is considered the strongest predictor of decompensation in these patients. However, due to its invasiveness and costs, CSPH is almost never evaluated in clinical practice. Therefore, recognizing non-invasively predicting tools still have more appeal across healthcare systems. The red cell distribution width to platelet ratio (RPR) has been reported to be an indicator of hepatic fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). However, its predictive role for the decompensation has never been explored., Aim: In this observational study, we investigated the clinical usage of RPR in predicting DEs in MASLD-related cACLD patients., Methods: Fourty controls and 150 MASLD-cACLD patients were consecutively enrolled and followed up (FUP) semiannually for 3 years. At baseline, biochemical, clinical, and Liver Stiffness Measurement (LSM), Child-Pugh (CP), Model for End-Stage Liver Disease (MELD), aspartate aminotransferase/platelet count ratio index (APRI), Fibrosis-4 (FIB-4), Albumin-Bilirubin (ALBI), ALBI-FIB-4, and RPR were collected. During FUP, DEs (timing and modaities) were recorded. CSPH was assessed at the baseline and on DE occurrence according to the available Clinical Practice Guidelines., Results: Of 150 MASLD-related cACLD patients, 43 (28.6%) progressed to dACLD at a median time of 28.9 months (29 NAD and 14 AD). Baseline RPR values were significantly higher in cACLD in comparison to controls, as well as MELD, CP, APRI, FIB-4, ALBI, ALBI-FIB-4, and LSM in dACLD-progressing compared to cACLD individuals [all P < 0.0001, except for FIB-4 ( P : 0.007) and ALBI ( P : 0.011)]. Receiving operator curve analysis revealed RPR > 0.472 and > 0.894 as the best cut-offs in the prediction respectively of 3-year first DE, as well as its superiority compared to the other non-invasive tools examined. RPR ( P : 0.02) and the presence of baseline-CSPH ( P : 0.04) were significantly and independently associated with the DE. Patients presenting baseline-CSPH and RPR > 0.472 showed higher risk of decompensation ( P : 0.0023)., Conclusion: Altogether these findings suggest the RPR as a valid and potentially applicable non-invasive tool in the prediction of timing and modalities of decompensation in MASLD-related cACLD patients., Competing Interests: Conflict-of-interest statement: The authors declare no competing interests., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose:  This multicenter retrospective study highlights the contrast-enhanced ultrasound (CEUS) findings in a series of histologically proven solitary necrotic nodules (SNN) of the liver, a poorly understood pathologic entity of uncertain origin that mimics malignancy., Materials and Methods:  22 patients (M/F 13/9; mean age 59.4 years, SD ± 10.7, range 35-81) with histological diagnosis of SNN and CEUS were selected from clinical, imaging, and pathological archives of 7 US interventional centers, each of which provided 1 to 6 cases (mean 2.8). Pathological diagnosis was made on 20 US-guided biopsies and 2 surgical specimens. 2 patients had 2 SNNs with identical CEUS findings so that imaging analysis was carried out on 24 nodules., Results:  SNN was an incidental finding in healthy people in 10 cases (45.5 %), and it was discovered during follow-up for either known extrahepatic malignancies (9 cases = 41 %) or chronic liver disease (3 cases = 13.5 %). SNNs had a mean size of 19.3 mm (SD ± 6.5, range 9-40). On B-mode US, SNNs appeared hypoechoic in 14 cases (66.7 %), "target-like" in 7 cases (29.2 %), and homogeneously hyperechoic in 1 case (4.1 %). On CEUS, all lesions appeared devoid of contrast enhancement ("punched out" aspect) in the arterial, portal venous, and late phases after US contrast agent injection. A uniformly thin, hyperenhancing ring in the early arterial phase and isoenhanced with the surrounding parenchyma in the portal venous and late phases was found in 10 nodules (41.6 %). Clinical and imaging follow-up (mean duration 42.2 months, SD ± 34.9, range 2-108) was available in 15 patients with 16 SNNs: no changes in size and echostructure were seen., Conclusion:  CEUS can contribute to the diagnosis of SNN when a "punched out" appearance in all vascular phases with or without thin rim enhancement in the very early arterial phase is present in healthy subjects in whom a focal liver lesion is incidentally found. In patients with a history of chronic liver disease or malignancy, US-guided biopsy represents the unavoidable first-line diagnostic modality., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)